Seminars in Cancer Biology 66 (2020) 171–181

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Autophagy in cancer: Recent advances and future directions T

a a b b,
Mohd Ishaq , Rani Ojha , Aditya P. Sharma , Shrawan K. Singh *
a
School of Medicine, Department of Pathology, Stanford University, CA, USA
b
Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

A R T I C LE I N FO A B S T R A C T

Keywords: Autophagy is being explored as a potential therapeutic target for enhancing the cytotoxic effects of che-
Autophagy motherapeutic regimens in various malignancies. Autophagy plays a very important role in cancer pathogenesis.
Cancer Here, we discuss the updates on the modulation of autophagy via dynamic interactions with different organelles
Therapy and the exploitation of selective autophagy for exploring therapeutic strategies. We further discuss the role of
Tumor immunity
autophagy inhibitors in cancer preclinical and clinical trials, novel autophagy inhibitors, and challenges likely to
Resistance
be faced by clinicians while inducting autophagy modulators in clinical practice.

1. Introduction transformed cells in adapting to the different cellular stress responses.

Autophagy is a multistep process that includes nucleation/
Macroautophagy, along with microautophagy and chaperone- Initiation, elongation, maturation, and recycling of the degraded com-
mediated autophagy are three catabolic processes involved in diverse ponents and membranous compartments [18,19]. Once the signal or
cellular functions [1,2]. During this process, autophagosomes sequester stimulus for autophagy is received, the initiation phase begins with the
the undesirable cytoplasmic contents and transfer them to the lysosome association of VPS34 (Vacuolar protein sorting 34) and Beclin-1, which
for proteolysis/degradation. Macroautophagy (hereafter autophagy) leads to the formation of phagophore [20]. The membrane source for
has progressed a lot, from being a simple double membrane structure phagophore remains debatable, as there are reports which suggest that
discovered by De Duve in 1960s to Yoshimori in 2016 [3]. From one mitochondria, plasma membrane, and even recycling endosomes may
Nobel laureate to another, the journey of autophagy has been quite contribute to the phagophore formation [21]. Once formed, phago-
fascinating and the status of autophagy has changed remarkably from phore acts as a docking site for the assembly of autophagy factors in-
being a simple catabolic process to one of the most complex processes volved in the elongation phase. During the elongation phase, the double
operating in the cells [4]. After the extensive research in last two membranous structure grows rapidly and sequesters the cargo for de-
decades, the functional significance of autophagy has also expanded gradation. Functionally elongation phase is the most crucial step be-
from a simple starvation response to various “controversial pair” roles cause it is during this step cargo is selected for the degradation. The set
like “anti-apoptotic or pro-apoptotic” [5–8], “Anti-tumorigenic or pro- of adaptors recruited on the elongating membrane determines the
tumorigenic” [9–11], “anti-bacterial or pro-bacterial” [12,13], “selec- nature of substrates to be engulfed and degraded in the subsequent
tive or non-selective” [14–16] and itself being a type of “cell death” or a steps of autophagy [22]. During the elongation phase, two ubiquitin-
“cell survival” mechanism. However, autophagy can be broadly defined conjugating systems (ATG7-ATG3 and ATG5-ATG12) lead to the con-
as an anti-stress process whose function depends upon the nature of version of LC3-I to LC3-II [23]. LC3-II discretely marks both inner and
stress, timing of stress, genetic makeup of the cells as well as on the the outer membrane of the autophagosome and acts as an anchor to
nature of the surrounding microenvironment. In general, if autophagy various autophagic adaptors like P62, NBR1 (Next to BRCA1 gene 1
is activated in normal cells, it acts as an anti-apoptotic mechanism, but protein), NDP52 (Nuclear domain 10 protein), Optineurin, VCP (Va-
if activated in abnormal cells, it may itself lead to cell death or activate losin-containing protein) via their LC3 interacting motifs [24]. Once the
apoptosis [17]. During the transition of normal cells to the tumor cells, cargo is selected and sequestered completely within the autophago-
autophagy may act as a strong barricade and effectively prevent this somes, the maturation step is initiated. Maturation involves the fusion
transformation. However, in the successfully transformed cells, autop- of autophagosome and lysosome to form the autolysosome. Rab7 along
hagy may act as a robust cellular process and help these newly with other proteins play important role in the trafficking of

⁎
Corresponding author at: Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
E-mail addresses: [email protected] (M. Ishaq), [email protected] (R. Ojha), [email protected] (A.P. Sharma),
[email protected] (S.K. Singh).

https://doi.org/10.1016/j.semcancer.2020.03.010
Received 15 February 2019; Received in revised form 10 February 2020; Accepted 16 March 2020
Available online 19 March 2020
1044-579X/ © 2020 Elsevier Ltd. All rights reserved.

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M. Ishaq, et al. Seminars in Cancer Biology 66 (2020) 171–181

autophagosomes towards the lysosome enriched regions of the cell machineries, and all of them can be degraded within the individual
(peri-nuclear regions) where SNARES (Soluble NSF Attachment Pro- autophagosomes [37,38]. Since mitochondria are the initiators of var-
tein) and other proteins complete the fusion process. Autophagy is ious cell death programs and main sources of ROS; the effective and
completed once the degraded products are released back into the cy- immediate clearance of defective mitochondria is crucial for cellular
toplasm and the membranous compartment restores its pH and is re- health and homeostasis. Once marked by the specific receptors such as
cycled back to the lysosome pool [18]. NIX, BNIP3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein
Evading cell death has been characterized as an important hallmark 3), P62, NBR1 (Neighbor of BRCA1 gene 1), Optineurin, and NDP52
of cancer cells. Cells follow different types of death programs when (Nuclear dot protein 52 kDa), etc. on their membranes, autophagy is
under stress, like apoptosis, necrosis, necroptosis, ferroptosis and so on very potent in clearing the defective mitochondria. In order to conserve
[25]. While autophagy is well known to play a cell survival role under and protect the physiologically active parts of the damaged mitochon-
stress or in response to various chemotherapeutic drugs but, there are dria, the damaged regions of mitochondria are specifically excised via
reports which suggest that autophagy can itself act as a form of cell the fission process and then degraded by mitophagy [39]. This also
death [26]. This type of cell death is called autophagic cell death and gives us a clear idea of how tightly mitophagy is regulated and syn-
may play an important role in developing novel cancer strategies. chronized with the fission process, that only a damaged portion of
During autophagic cell death, autophagic vesicles are accumulated in- mitochondria is engulfed by autophagosomes. Targeting the mitophagy
side the cytoplasm and many of the Atg proteins play an active role in is a promising anti-cancer therapeutic strategy [38–40]. Although mi-
the induction of autophagic cell death. This type of cell death is highly tophagy has been generally considered as a cell protective mechanism,
context-dependent and has been specifically found upregulated in the both mitophagy inhibition and induction have been implicated in reg-
apoptosis-resistant cells [27–30]. Apoptosis resistant, Bax/Bak deficient ulating tumor growth. For example, inhibition of mitophagy in KRAS-
cells undergo autophagic cell death upon treatment with therapeutic driven cancers and melanoma can be a potential target to sensitize
drugs [31]. Also, inhibition of caspase-8 one of the key proteins in- these tumors to therapy [41]. Salinomycin and Liensinine are known to
volved in the intrinsic apoptotic pathway results in the induction of inhibit mitophagy [42] and have been reported to enhance the sensi-
autophagic cell death which is dependent on Beclin-1 and Atg7 [32]. In tivity of breast cancer cells to various DNA damaging chemotherapeutic
contrast to caspase-8, activation of caspase-10 in myeloma cells inhibits drugs [43]. In colorectal cancer stem cells inhibition of mitophagy by
the induction of autophagic cell death by cleaving the BCLAF1 (BCL2- BNIP3L knockdown enhances doxorubicin (DNA damaging agent)
associated transcription factor 1) protein [33]. Autophagic cell death sensitivity. In contrast, the negative regulator of mitophagy, USP30
offers a unique window of therapeutic potential, as cancer cells are (Ubiquitin Specific Peptidase 30), represents a potential target whose
highly resistant to apoptosis. Therefore, drugs inducing autophagic cell inhibition can increase mitophagy, and suppress tumor growth [44].
death can be useful in managing the apoptosis-resistant cancers. Also, Also, the adverse tumor-promoting effect of chronic mitophagy in-
most of the cancer cells become resistant to common anticancer drugs, hibition has been observed by deletion or inactivation of genes PARKIN
which act via the initiation of apoptosis or necroptosis. But autophagic and BNIP3 [45]. Mitophagy may be the common mechanism to increase
cell death can be induced in these resistant cancer cells as well. drug resistance and promote tumor survival, and accordingly, mito-
Therefore, both inhibition and induction of autophagy should be con- phagy inhibition may be a general strategy to decrease drug resistance
sidered as therapeutic interventions. In addition, non-canonical au- [46]. However, there are reports, which suggest that mitophagy in-
tophagy has also been shown to contribute to cell death through a duction may be a therapeutically relevant strategy as well. For example,
process that is independent of the entire machinery of Atg proteins excessive mitophagy induced by ceramide by directly interacting with
[34]. Currently, autophagy inhibitor hydroxychloroquine (HCQ) is in LC3 has been shown to be a tumor suppressor mechanism in xenograft
phase I and II clinical trials in combination with several standard che- models. Ceramide induced mitophagy depends on mitochondrial fission
motherapies while autophagy induction remains to be tested clinically [47]. Similarly, FLT3-ITD (Fms-like tyrosine kinase 3–internal tandem
[28]. Therefore, an in-depth understanding of the roles of autophagy duplication) signaling axis acts as a resistance mechanism in AML
during different stages of carcinogenesis has a unique potential to guide (acute myeloid leukemia). The FLT3 provides resistance by limiting the
the development of therapeutic strategies to eliminate cancer cells, ceramide generation and accumulation on the mitochondrial outer
prevent drug resistance and also stop recurrence. membrane. Targeting FLT3 signaling activated ceramide-induced lethal
mitophagy and effectively evaded the drug resistance mechanism [48].
2. Selective autophagy and cancer: a window to novel target Similarly, a small molecule activator of SITR1 (Sirtuin-1) has been
shown to induce the mitophagy related cell death in glioblastoma [49].
Selective or cargo-specific autophagy has been shown to play a pi-
votal role in various pathological conditions including cancer. Recently, 2.2. Reticulophagy
various selective forms of autophagy have been reported such as nu-
cleophagy, RNAphagy, ferrtinophagy, etc. (Fig. 1). However, further ER (Endoplasmic Reticulum) comprised of interconnected mem-
research is required to prove a more direct association of these newly branous sheets that facilitate protein and lipid biosynthesis, proteins
discovered selective forms of autophagy and disease progression. Re- quality control, regulates vesicles trafficking, and ion homoeostasis
cently, various studies have highlighted the importance of selective [50,51]. During stress or unfavorable conditions, some proteins become
forms of autophagy like mitophagy, reticulophagy, and ribophagy as misfolded/aggregated and get accumulated in the lumen of the ER,
druggable targets. In this section, we will discuss different forms of leading to ER stress [52,53]. During ER stress two interrelated quality
selective autophagy, their importance and role in cancer cells and how control pathways- the UPR (unfolded protein response) and the ERAD
these processes can be manipulated for better therapeutic interventions. (ER-associated protein degradation) [54] pathways are activated. UPR
activation increases the folding capacity of the ER [55,56], whereas the
2.1. Mitophagy ERAD system recognizes terminally misfolded proteins and facilitates
their translocation back into the cytoplasm from the ER. In the cyto-
Mitochondria are the central hubs of cell death, metabolism, im- plasm, these misfolded proteins are then degraded by the ubiquitin-
mune surveillance, reactive oxygen species (ROS) and adenosine tri- proteasome system [57]. The UPR induces various regulatory molecules
phosphate (ATP) production [35,36]. Autophagy has an advantage over that sense elevated levels of unfolded and aggregated proteins in the
ubiquitin-proteasome system that can degrade an organelle as a whole lumen and activates downstream PERK-eIF2α signaling pathway to
without disassembling it to its constituent macromolecules. For in- attenuate the global translation. The same pathway also leads to the up-
stance, mitochondria have their own genomes and translation regulation of transcription of ER stress response genes (such as ATF4,

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Fig. 1. Different types of selective autophagy in mammalian cells. Selective autophagy represents the recognition and degradation of specific cargo. Selective
autophagy receptors for the respective processes are listed. The question mark indicates yet to unidentified receptor proteins.

ATF3, CHOP, CCNG2, GADD34, etc.) and restores the ER health and the RTN3 oligomerization. RTN3 oligomerization leads to the ER-
homeostasis [56]. fragmentation and subsequent lysosomal degradation via the autop-
Various groups have shown the interconnection between ER stress hagy-lysosomal pathway.
and cancer. Moreover, the UPR plays an important role in resistance SEC62 is a subunit of the SEC translocation machinery involved in
mechanisms against cancer therapy [58]. UPR induction has been the transport of newly synthesized proteins into the ER. Recently,
known to increase the autophagy via upregulation of ATG genes SEC62 is reported to function as an autophagy receptor during the re-
[59–61]. Interestingly, it has been shown that the accumulation of covery phase after ER stress [76]. SEC62 is located at the rough ER and
aggregated/misfolded proteins in the ER lumen leads to removal of the selectively delivers those portions of ER, which are enriched in the
ER fragment via autophagy, which also known as reticulophagy/ER- molecular chaperones and other such proteins after UPR. The function
phagy [62–64]. Just like the mitophagy, six specific ER-phagy receptors of SEC62 mediated reticulophagy is to restore the ER to the basal
have been reported- Sec62 [65], FAM134B [66], CCPG1 (cell-cycle condition after the ER stress response is over [76]. SEC62 is frequently
progression gene 1) [67], RTN3 (reticulon3) [68], ATL3 (Atlastins) [69] amplified in non-small cell lung, prostate, thyroid cancers, and head
and TEX264 [70]. The cytoplasmic sides of these receptors contain and neck cancers [77]. In addition, a recent study by Ojha et al. have
LC3/GABARAP interacting region, which helps them to bind with au- shown that SEC61 allows translocation of BRAF-MEK-ERK signaling
tophagosomes. These receptors have a distinct spatial distribution on axis into the ER lumen during BRAF and MEK inhibition treatment.
the ER and are therefore involved in ER-phagy of the different ER Interestingly, inhibition of SEC61 translocon blocks autophagy and
compartments. FAM134B is enriched at the edges of ER-sheets and induces cancer cell death in melanoma cells [78]. CCPG1, an ER-re-
helps in the autophagic degradation of fragmented portions of ER. sident transmembrane protein, contains a LIR at the N-terminal cyto-
FAM134B itself is involved in the fragmentation of ER-sheets via its RH solic domain which binds with LC3/GABARAP [79,80]. CCPG1 is
domains and in selectively targeting these ER-fragments to autopha- mainly localized on tubular-ER and is therefore involved in the au-
gosomes by its LC3/GABARAP interacting regions. Inhibition of tophagic degradation of tubular portions of the ER. CCPG1 is unique
FAM134B increased swelling and expansion of the ER, while over- among the known ER-phagy receptors as it also contains two FIRs
expression of FAM134B led to ER fragmentation and degradation [71] (FIP200 interacting regions) apart from LC3 and GABARAP binding
by reticulophagy. FAM134B is involved in various cellular signaling sites. These FIRs can directly recruit the FIP200-ULK complex and in-
and plays key roles in the pathogenesis of different human diseases itiate the autophagy directly. Although these studies do suggest the role
including cancer [72]. Interestingly, FAM134B acts as an oncogene and of reticulophagy in cancer, but further studies in preclinical models are
stimulates esophageal squamous cell carcinoma cell growth and pro- required to make reticulophagy as a druggable target. ATL3 is also the
liferation, on the other hand, it acts as a tumor suppressor and reduces autophagic adaptor for tubular-ER and belongs to the dynamin-like
colorectal adenocarcinomas cancer cells growth and proliferation [72]. GTPase family. ATL3 only contains GIMs (GABARAP interacting motif)
FAM134B mutations are common in esophageal squamous cell carci- but not the LIRs. TEX264 is the latest addition of ER-phagy receptor
noma and colorectal adenocarcinomas [73,74]. RTN3 as a new re- family. TEX264 has been shown to be the most robust of all the ER-
ticulophagy receptor, involved in the selective degradation of ER tu- phagy receptors and is accordingly is found uniformly distributed on
bules [75]. RTN3 is selectively enriched at the curved ends of ER- the ER. This leads to the speculation that drugs blocking autophagy
tubules and any increase in the local concentration of RTN3 results in could be an advantageous component of chemotherapeutic regimens

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aiming at counteracting the protective effects of SEC62 overexpression ribosomes in malignant transformation is becoming more obvious, the
in tumors. drugs targeting ribosome biogenesis may become very useful in tar-
geting cancer cells with hyperactive ribosomes.
2.3. Ribophagy
3. Selective autophagy, and clinical translation
Ribosomes were found inside the autophagosomes by electron mi-
croscopy in 1960 and were believed to be passively engulfed by au- 3.1. Autophagy and the web of inter-organelle membrane contact sites
tophagosomes along with the other cytoplasmic contents [81–83]. De-
gradation of ribosomes via autophagy (ribophagy) was well established In the past few decades cell biologists have now well established
by Kraft et al. as a distinct process than the bulk nonselective autophagy that cellular organelle like mitochondria, endoplasmic reticulum, en-
during nutrient starvation [84]. Ribosomes are very stable molecules dosomes etc. are interconnected with each other via the structures
with a half-life of several days and comprise almost about 50% protein called as membrane contact sites (MCS). MCS are well-defined struc-
in normally growing cells. During nutrient starvation, cells can easily tures where the membranes of two organelles are in close proximity
degrade the highly stable ribosomes and respond to cellular stress in an (10-50 nm) and are held together by specific proteins called as tethering
effective way. Lessons from the mitophagy do provide the insights that proteins. These MCS sites act as signaling hubs and are also involved in
ribophagy may be a selective process and almost a decade later, the first diverse functions like trafficking of lipids and ions [100]. The ER forms
ribophagy receptor was hunted down by the Sabatini group in 2018 MCS with mitochondria, endosomes, and autophagosomes, therefore a
[85]. Most of the autophagy receptors interact with LC3 via their LIR specific set of proteins are enriched at ER-mitochondria, ER-endosomes,
domains and ribophagy receptor, NUFIP1 (nuclear fragile X mental and ER-autophagosomes contact sites [101]. Similarly, the mitochon-
retardation–interacting protein 1) proved no exception to that. NUFIP1 dria itself is also connected with lysosomes, endosomes, lipid droplets
via interacting with LC3 helps in the degradation of ribosomes and and peroxisomes. The ER-MCS have very specific functions and re-
leads to cell survival during starvation. cently, ER-mitochondria and ER-plasma membrane contact sites have
Both 60s and 40s ribosomal subunits are synthesized in the nu- been shown to act as a source of autophagosomes biogenesis [102,103].
cleolus, exported into the cytoplasm where they are finally assembled VMP-1 (Vacuole membrane protein 1), an ER-resident protein regulates
into the mature 80s subunit by the help of accessory proteins [86,87]. the ER-MCS and acts as a positive regulator of autophagosome bio-
The cancer biologists already were aware of the alterations in nucleolus genesis [104–106]. The ER-MCS and autophagosomes biogenesis are
size, number, and morphology, but the importance of the ribosome it- intricately linked as VMP1 inhibition increases the number of ER-MCS
self was not recognized in cancer cells [88]. Cancerous cells, in general, but blocks autophagosome formation. During the loss of ER-MCS sig-
have the high ribosome biogenesis and are believed to be addicted to naling, cells dependent on other stress response systems, to maintain
the ribosomes as well [89]. This seems logically simple, as cancer cells organelle homeostasis and integrity [107,108]. ER-mitochondria con-
are rapidly dividing and therefore in need of a constant supply of the tact sites are at the center of metabolic regulation and cell stress re-
proteins necessary for growth and proliferation. Also, most of the active sponse. Mitochondria are in contact with both smooth ER and rough
signaling cascades in cancerous cells positively regulate ribosome bio- ER, but the functional significance of rough ER-mitochondria is not
genesis. However, there is evidence that suggests that increased ribo- clear yet. Smooth ER-mitochondria contact sites are involved in Ca2+
some numbers can itself lead to cancer [90]. Various studies have lipid transport across the two organelles. There are several other ways
shown the increased ribosomal number is upstream of the oncogenic by which ER-Mitochondria may be involved in cancer progression and
signaling cascades [91]. Ribosomes were thought to be very static nano- drug resistance and have been excellently reviewed by Doghman and
machines that statically translated the genome. Ribosomes, in general, Lalli [109]. Here we will be mainly focusing on the relationship of
were thought to be highly regulated molecular machines without autophagy with ER-mitochondria contact sites and its role in cancer
having any regulatory function of their own. However, there is now progression and drug resistance. ER-mitochondria contact sites have
evidence that cancer cells during the malignant transformation may been reported to overcome the cisplatin resistance by increasing cal-
acquire the property of assembling the specialized ribosomes [92,93]. cium transport from ER to mitochondria in colorectal cancer cells
But, how do cancer cells maintain these specialized ribosomes will be [110]. Bcl2 overexpression decreases the cisplatin sensitivity of ovarian
very critical for proper cancer cell proliferation and is one of the most cancer cells by decreasing the ER-mitochondria contact sites SKVO3
critical questions among the cancer biologists. cells [111].
Rack1 (Receptor for Activated C Kinase 1) interacts with the 40s ER is also in contact with the endosomes and these contact sites are
ribosomal subunit and acts as an adaptor for various signaling mole- quite distinct from the ER-mitochondria contact sites. At the site of
cules. Rack1 deficient ribosomes have been shown to increase the ex- endosome-ER contact, a distance of 10 nM only separates the two
pression of genes involved in non-canonical autophagy [94,95]. The membranes [112]. ER-endosome contact sites regulate the position,
function of Rack1 depends on its interacting proteins so Rack1 may play dynamics, and fission of the endosomes. VAPA, VAPB, MOSPD2,
a central role in linking autophagy and ribosome function. Rack1 has STARD3, and STARD3NL are the key proteins involved in the main-
been also shown to directly interact with the Atg5 [73] and also pro- tenance of the ER-endosome contact sites [113–115]. VAPA and VAPB
mote autophagy by VPS34 complex formation [96]. Recently, Sundar- are integral ER membrane proteins and have been recently reported to
amoorthy et al elucidated the role of Rack1 in ribosomal quality control directly involved in autophagy by helping in the formation of Isolation
(RQC) by regulating the ubiquitination of 40s ribosomal subunit. Ri- membrane [116]. VAPA and VAPB directly interact with the ULK-
bosomal ubiquitination is now emerging at the center of ribosome FIP200 via their FFAT motifs. ER has been also shown to form contacts
quality control [97]. In fact, the autophagy-mediated degradation of with lysosomes for the maintenance of calcium levels in the cell. The
ribosomes is also regulated by ubiquitin protease. It is very important to interaction is specifically mediated by the IP3Rs and these receptors are
note that the de-ubiquitination of ribosomal subunits serves the signal also involved in translocation of calcium from ER into the lysosomes
for ribophagy. Listerin1 is one of the crucial RQC factors that is a [117].
ubiquitin ligase and effectively inhibits the ribophagy [98]. Listerin1 is In conclusion, the MCS are at the center of cellular signaling, me-
involved in the degradation of polypeptide chains associated with tabolism, growth and cell death. Autophagosome biogenesis depending
stalled ribosomes [99]. Since post-translational modifications act as on the stimulus is initiated at ER-mitochondria contact sites, plasma
molecular signatures for selective autophagy degradation therefore the membrane, ER, recycling endosomes. Specific autophagy receptors are
association of Rack1, Listerin1 and other adaptors may be also crucial localized on the ER and on the mitochondria and may fine-tune the
for the regulation of ribosomal function. As the importance of drug resistance mechanisms in cancer cells. Targeting the MCS enriched

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proteins along with the conventional anticancer agents may be the next- regulators of cellular metabolism and autophagy is one of the key
generation strategy in treating drug-resistant cancers. Further studies processes that maintain the healthy pool of the mitochondria. By reg-
are needed to define the MCS, autophagy and their dynamics under ulating the mitochondrial number autophagy indirectly contributes
different stress conditions. The regulatory loops and specificity of pro- towards maintaining the key metabolic intermediates. The final stages
teins enriched at mitochondria-ER-autophagosome biogenesis sites and of autophagy involve the recycling of digested intracellular components
other contact sites will provide a better understanding of the role with the help of lysosomes. So, autophagy is also directly involved in
played by autophagy in tumor progression and particularly in drug metabolic regulation by degrading various complex macromolecules
resistance mechanisms. into their smaller subunits. Accordingly, cancer cells are mostly ad-
dicted to functional autophagy and deletion of autophagy genes impair
3.2. Autophagy in cancer stem cells the tumor growth in melanoma [135], urothelial carcinoma, non-small-
cell lung cancer cells and a mouse model for allografts of melanoma
Cancer Stem Cells (CSCs) are reported to have higher autophagic [136]. Autophagy can recycle back amino acids, carbohydrates, and
flux compared to bulk tumor cells [118,119]. Various ATG genes are nucleotides that can essentially maintain all the central metabolic
highly expressed in CSCs for the maintenance of CSCs dormancy. The pathways like the tricarboxylic acid cycle (TCA) cycle and glycolysis.
increased autophagic flux has been reported to play a major role in CSC Since the cancer cells are limited by the availability of nutrients, au-
mediated development of tumorigenesis in leukemia [120] and breast tophagy can provide essential metabolites and act as a buffering system
cancer [121]. Additionally, autophagy induction provides resistance to during nutritional scarcity. Autophagy has been shown to play an im-
photodynamic therapy in CSCs [122], leading to the recurrence and portant role in maintaining glycolysis in breast cancer cells, chronic
progression of colorectal cancer [123]. Recently, autophagy has shown myeloid leukemia, and Ras-driven cancers [137,138]. The levels of
to play an adverse role in osimertinib induced cytotoxicity by inducing various metabolic intermediates have also been reported to inhibit or
stem cell-like properties in non-small cell lung carcinoma. Combined induce autophagy. High glucose levels in pancreatic cancer patients
treatment of epidermal growth factor receptor-tyrosin kinase inhibitor were recently reported to inhibit autophagy via SREBP1 and lead to the
and autophagy inhibitor inhibits the stemness and restored the toxicity poor disease prognosis [139].
of osimertinib [124]. On the contrary, the increased autophagy induced Acetyl-CoA acts as an autophagy inhibitor via the acetyltransferase
by nigericin has been shown to suppress CSCs characteristics in glioma EP300 [140]. Acetyl-CoA is a key metabolic intermediate involved in
cells [125]. Both autophagy and CSCs are the two arsenals deployed by the regulation of autophagy. Acetyl-CoA depletion induces autophagy
various tumors for the development of drug resistance [126], therefore while increasing its concentration even under starvation can effectively
the underlying regulatory mechanism between these two factors may be inhibit autophagy [140]. Acetyl-CoA pool in cells is generated via
critical for the development of new drug combinations. In this aspect, glycolysis or by the degradation of some amino acids, both of which are
our lab has previously reported that the treatment of CQ (chloroquine), among the key regulators of autophagy. Recently, Lee et al have shown
a well know autophagy inhibitor, increases the sensitivity towards that in glioblastoma cells acetyl-CoA can up-regulate the genes involved
gemcitabine and mitomycin [127]. Another study also demonstrated in cell migration- and adhesion via Ca2+–NFAT (nuclear factor of ac-
that CQ reduces CSCs populations in triple-negative breast CSCs [128]. tivated T cells 1) signaling axis. The crosstalk between a metabolic
Similarly, salinomycin by inhibiting autophagy has also been reported intermediate Acetyl-CoA and Autophagy may be key in determining
to reduce the proportion of breast CSC population [129,130]. Also, tumor development and metastasis. Accordingly, the autophagy-Acetyl-
salinomycin has shown to inhibit autophagy under conditions of tran- CoA-NFAT axis may be, therefore, exploited as a potential anticancer
sient and chronic acidosis. This study suggested that the development strategy [141]. Apart from glycolysis, inhibition of autophagy by CQ
and use of clinically suitable derivates of salinomycin may improve the has been shown to decreases the oxidative phosphorylation in pan-
efficacy of autophagy inhibition in the acidic tumor microenvironment creatic cancer cells [142]. In Atg7-null mice, studies have shown the
[129]. increasing circulating metabolites differently regulated compared to
Recently, drug-loaded albumin coated nanoparticle has shown to Atg7+/+ mice. Arginine was highly down-regulated in Atg7Δ/Δ mice
facilitate efficient targeted therapy in glioma CSCs during the combi- [143], providing a direct link between amino acid metabolism and
nation of chemotherapy and autophagy [131]. In addition, the en- autophagy. Further studies in mice models may provide details on how
dosomal pathway has shown to be involved in the maintenance and autophagy regulates and supplies growth-limiting factors to the cancer
survival of cancer stem cells in colorectal cancer. A combination of cells under hypoxia, ischemia and other stressful condition.
mefloquine hydrochloride, a novel RAB5/7 inhibitor with chemother-
apeutic agent-induced colorectal cancer cell death [132]. In addition, 3.4. Autophagy in tumor immunity
autophagy has shown to play an important role in the maintenance of
CSCs by the regulation of immune cells and cytokine production. Au- Autophagy has been well known to play a role in antibacterial and
tophagy inhibition modified CD44high/CD25low population in breast viral immunity [144]. Also, in Atg7-null mice, an increased antitumor
CSCs by regulating CD24 and IL-6 in autophagy-dependent breast immune response was observed, indicating as a potential reason for
cancer [133]. Autophagy gene ATG7 induced OCT4 transcription via β- reduced tumor growth [145]. Functional autophagy is necessary for the
catenin to facilitates characteristics of CSCs in prostate cancer. CSCs survival and development of NK (Natural Killer) cells, and neutrophils
maintain their characteristics by modifying monocytes/macrophages in antitumor immune response and in tumor microenvironment
toward tumor-associated macrophages to provide resistance to prostate [146,147], and is also required for the effective onset of DC (dendritic
cancer via IL6/STAT3 [134]. Altogether, the role of autophagy in CSCs cells) mediated adaptive anticancer immunity. However, the deletion of
may not be as straight forward as thought earlier, however targeting ATG5 in DCs does not affect the presentation of tumor-associated an-
autophagy and CSCs may be a potent way to block tumor drug re- tigens on MHC- I molecules [148]. In addition, Treg cells by inhibiting
sistance and recurrence. CSCs can be a cause of therapeutic escape autophagy are reported to suppress autoimmune response in DCs. Au-
leading to tumor recurrence and relapse. Controlling the recruitment tophagy has shown to be upregulated in patients and mouse models of
and sustenance of CSCs has been achieved with autophagy inhibitors. melanoma. Inhibition of autophagy in myeloid cells decreased tumor
growth and induce an anti-tumor immune response in vivo. Autophagy
3.3. Autophagy in cancer metabolism deficient MDSCs (Myeloid-derived suppressor cells) showed decreased
expression of the membrane-associated RING-CH1 (MARCH1) E3 ubi-
Autophagy contributes both directly and indirectly in maintaining quitin ligase that mediates the lysosomal degradation, which led to
the metabolic pool of cancer cells. Mitochondria are the central enhance the surface expression of MHC-II and thereby induce tumor-

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M. Ishaq, et al. Seminars in Cancer Biology 66 (2020) 171–181

specific CD4-T cells. This study illustrates that autophagy may be a promote apoptosis by inhibition of autophagy [161]. The initial phase
potential druggable target of MDSCs-mediated suppression of antitumor I/II trials of HCQ have been on adult solid tumors [162]. These included
immunity, however, this study did not correlate with in vivo findings studies on patients with pancreatic adenocarcinoma, melanoma, col-
[149]. Recently, genetic inhibition of BECN1 has shown to inhibit orectal carcinoma, myeloma, lymphoma, and renal cell carcinoma. The
tumor growth by overexpression and release of CCL5 cytokine via chemotherapeutic drugs used were temsirolimus, bortezomib, temozo-
MAPK8/JNK-JUN/c-Jun signaling pathway, leading to massive NK cells lomide, vorinostat, and doxorubicin [163–169]. The cancer patients
infiltrations into the tumor microenvironment. More importantly, the received HCQ in the range of 400 mg–600 mg BD. The study found the
authors demonstrated a strong clinical positive correlation between the dosages to be well tolerated with partial response and stable disease in a
expression of NK cell marker and CCL5 in melanoma patients and found subset of population [170]. 1200 mg /day is the highest possible dose
a significant increased survival in melanoma patients expressing a high approved by food and drug administration and these trials established
level of CCL5. Overall, these findings emphasize the importance of the safety profile of HCQ in combination with cytotoxic drugs in solid
autophagy inhibition in the exploitation of NK cell-mediated anti-tumor tumors [170]. HCQ was used in combination with 150 mg/m2 of te-
immunity [150]. mozolomide in advanced solid malignancies and melanoma [171].
In addition, the deletion of autophagy genes Atg5, Atg14, or Atg16l1 Rangwala et al. showed a 27 % stable disease and 14 % partial response
has shown to impair tumor growth in autophagy-competent syngeneic in wild type melanoma [165,166]. The combination of HCQ produced
mammary, prostate, and colorectal tumors [151]. The authors further synergistic activity with rapamycin by suppressing mTORC1 activity.
demonstrated that Atg5 deficient CD8+ T cells acquire an effector The mTOR inhibitor temsirolimus was used in combination with HCQ
memory phenotype. These phenotypic changes are mediated by en- in phase I trial by the same group in advanced solid tumors [164]. The
hanced glucose metabolism resulting in alterations in histone methy- combination was well tolerated with limited side effects. Vogl et al.
lation which increases in H3K4me3 density and leads to the upregula- treated 25 myeloma patients with bortezomib in combination with HCQ
tion of both metabolic and effector target genes. Interestingly, [164]. Autophagy inhibition with HCQ enhances the efficacy of pro-
regardless of the significant reduction in total CD8 + TILs (tumor-in- teasome inhibitor by leading to the accumulation of misfolded proteins
filtrating cells), Atg5 deficiency leads to a significant shift towards IFN- [134]. Forty-five percent of patients showed stable disease as their best
γ- and TNF-α-producing effector memory cells. However, restricting response. The most common adverse events in this trial were gastro-
glucose in Atg5−/− T cells and adoptive transfer with a sub-therapeutic intestinal and cytopenias [164]. Sorafenib is a multi tyrosine kinase
dose of atg5−/− T cells significantly decreased the tumor growth and mTOR inhibitor, which has been used in hepatocellular carcinoma
reduced the tumor volume. This finding highlights the unique role of [169]. It has been found to induce autophagy and the same is being
cell-autonomous T cell autophagy in anti-tumor immune response in investigated as the cause of possible drug resistance. Two important
cancer [151]. Recently, Chen at al shown that autophagy inhibitor CQ clinical trials (Table 1) are studying the use of HCQ in hepatocellular
(chloroquine) increases macrophage lysosomal pH which leads to ly- carcinoma. HCQ, when used at high doses and for a longer duration,
sosomal Ca2+ release, polarizing tumor-associated macrophages from showed retinal toxicity. Thus, baseline retinal screening and annual
M2 to M1 phenotype [152]. This study highlighted yet another me- screening after five years has been recommended for early detection of
chanism of CQ as a potent immunotherapeutic modulator in cancer changes [171]. Targeted immunotherapeutic agents including check-
cells. Moreover, PDI inhibition leads to the induction of autophagy point inhibitors have limited efficacy and are expensive. If the efficacy
which may be a factor towards the resistance to the anti-PDI antibody
by tumor cells [153,154]. Therefore, autophagy inhibitors like CQ may
Table 1
be an effective way to increase the efficacy of immunotherapy. How-
Summary of clinical trials on autophagy in cancer.
ever further in-depth studies are needed to establish the role of PD1 and
autophagy in modulating the anti-immune response. Cancer Autophagy Clinical Trial registration
Modulators trial phase number

4. Clinical perspective Pancreatic HCQ + gemcitabine Phase I/II NCT01128296

carcinoma
The role of autophagy in cancer development, progression, metas- HCQ + Gemciatbine/ Phase I/II NCT01506973
tasis, resistance, and recurrence has been now proved by multiple abraxane
HCQ Phase I/II NCT01273805
studies, but the progress in clinical frontiers has recently gained mo- HCQ + Capecitabine Phase I/II NCT01494155
mentum. Autophagy inhibitors have been shown to have synergistic HCQ + gemcitabine Phase I/II NCT01978184
actions with chemotherapeutic agents and targeted immunotherapeutic + nab-paclitaxel
agents. A number of candidate compounds that inhibit autophagy are in Hepatocellular Sirolimus Phase II/III NCT00328770
carcinoma
process of development, however, the approved compound presently is
Sirolimus Phase II NCT01079767
only CQ and its derivative HCQ [155]. HCQ like CQ inhibits autophagy Everolimus Phase III NCT01035229
by preventing lysosomal acidification and degradation of autophago- Sorafenib Phase III NCT00105443
some [155–157]. HCQ became the drug of choice over CQ as it has Sorafenib Phase III NCT00492752
lesser toxicity as compared to CQ [157–160]. There has been enough Sorafenib+HCQ Phase II NCT03037437
HCQ Phase I/II NCT02013778
evidence from the preclinical and animal studies that HCQ will prevent Sirolimus Phase II/III NCT00328770
chemoresistance. In bladder cancer cell lines, Ojha et al. has shown that Lung Cancer HCQ Phase I NCT01026844
a combination of HCQ with gemcitabine and mitomycin inhibits au- HCQ + Erlotinib Phase I NCT01026844
tophagy and prevents tumor spheroid formation and decreased stem- HCQ + Erlotinib Phase II NCT00977470
Breast Cancer HCQ + Ixabepilone Phase I/II NCT00765765
ness [127]. The autophagy inhibition by HCQ may enhance the effect of
CQ + Taxane Phase I NCT01446016
chemotherapy and prevent consequential tumor progression and tumor CQ Phase I/II NCT01023477
recurrence. Based on these preliminary results a Phase II trial has been CQ Phase I NCT02333890
designed for muscle-invasive bladder cancer combining HCQ with Renal Cell HCQ + Interleukin 2 Phase I/II NCT01550367
gemcitabine and cisplatin for systemic chemotherapy (unpublished Carcinoma
Bladder Cancer HCQ + gemcitabine Phase II/III CTRI/2018/06/
data: CTRI/2018/06/014652). Similarly, in breast cancer combination and cisplatin 014652
of HCQ with tamoxifen was found to be more effective in inhibiting
autophagy in estrogen-positive (ER+) cell lines [160]. In renal cell HCQ- Hydroxychloroquine.
carcinoma, HCQ combined with temsirolimus has been found to CQ- Chloroquine.

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M. Ishaq, et al. Seminars in Cancer Biology 66 (2020) 171–181

Fig. 2. Autophagy process, activators, inhibitors, and druggable targets. Nutrient starvation, growth factor deprivation is known to induce autophagy flux. These
factors lead to an increase in mTORC1 inhibition and AMPK activation. This initiates the upregulation of ULK1 complex through a series of phosphorylation cascades.
The membranes of isolation membrane/phagophore have multiple sources such as the ER, endosomal compartment, mitochondria, and plasma membrane. LC3
lipidation sites for autophagosome precursors by the recruitment of the two-ubiquitin ligase complexes. This step leads to the elongation of the phagosphore. The
autophagy process ends up by degradation of engulfed substrates in the lysosome after fusion with autophagosomes. Specific autophagy inducers and inhibitors are
also shown in the figures.

of autophagy modulators such as HCQ is proven to be worth, the Selective autophagy has opened a new therapeutic window for ef-
treatment can be made more cost-effective. fective cancer treatment. Different cancers are addicted and more
The various signaling cascades upstream of the phagophore, pro- sensitive to one process than the other. Therefore, targeting mitophagy,
teins involved in different steps of autophagy and factors regulating the reticulophagy, and ribophagy via their respective receptors can be ex-
end stages (lysosomes), have all been exploited for the therapeutic in- plored for widening to therapy alternatives.
terventions (Fig. 2). Various inhibitors have been reported by re-
searchers to target autophagy at different stages in different cancers. 5. Future challenges
These inhibitors may be considered as potential therapeutic molecules
against various cancers. First, targeting upstream signaling molecules: Autophagy modulation studies on tumor cell lines and mouse
inhibitors include SBI-0206965, inhibitor of the autophagy kinase ULK1 models have already led to the discovery of novel chemotherapeutic
(Unc-51 like autophagy activating kinase), Spautin-1, a class III PI3 strategies. There are lots of autophagy modulators in different phases of
kinase complex and Beclin1 inhibitor [172], SAR405, a kinase inhibitor clinical trials but several questions from clinical aspects remain to be
of Vps18 [172], Gambogic acid a natural anticancer agent induces answered. First and foremost, how to monitor the levels of autophagy
Caspase mediated cleavage of autophagy proteins involved in initiation inhibition or induction in patients treated with autophagy modulators?
and elongation phages of autophagosomes biogenesis [8]. Second, au- Once the autophagy is inhibited, how can we evaluate the status of
tophagy initiation inhibitors; ATG4 inhibitors, NSC185058 and autophagy in tumor subpopulations? To obtain all tumor cells in a
NSC377071 [173], Verteporfin, inhibits autophagosome formation at particular phase of cell cycle is another bone of contention in tapping
an early stage [174]. Third, lysosomal inhibitors: ROC325 [175], Lys05 the advantage of autophagy modulation. Predicting the outcome of
[176]. DQ661 [177] and DC661 [178] are new potential lysosomal- already existing anticancer drugs in combination with different au-
autophagy inhibitors. In addition, Autophagy has also been studied in tophagy inhibitors can be very useful in developing better treatment
potentiating the radiotherapy and as radiosensitizer in preclinical trials strategies. Classification of tumors, which are best served by autophagy
[179–181]. Woon Kim et al. studied autophagy induction in cells and inhibition or by autophagy induction is still a dillema. Identification of
mouse model of lung cancer using Z-DEVD (caspase-3 inhibitor), some markers which can predict whether autophagy is a pro-survival or
RAD001 (mTOR inhibitor) and irradiation. They found that the greatest pro-death process in specific cancer will be of immense importance for
induction of autophagy and associated radiation toxicity was observed effective treatment strategies. Identifying which role of autophagy (pro-
in the treatment group where all the three modalities were used si- survival or pro-death) is dominant in particular cancer, and at which
multaneously. They suggested that combined inhibition of apoptosis stage of tumor development autophagy should be targeted are two
and mTOR during radiotherapy may be a potential therapeutic strategy pertinent questions.Finally autophagy is a normal homeostatic reg-
to enhance radiation therapy in patients with non-small cell lung cancer ulatory mechnism of tissues. The inhibition of this mechanism can lead
[180]. Similarly, in glioma cells Wu et al. found that cell protective to lysosomal storage diseases, neurodegenerative disorders, diabetes
autophagy could be induced by AgNPs and/or radiation, which was and liver dysfunction. Similar to chemotherapetic drugs the con-
verified by the use of 3-MA [181]. comitant autophagy modulators affect the normal tissues and are not

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M. Ishaq, et al. Seminars in Cancer Biology 66 (2020) 171–181

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