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Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105 Page 7 of 25

suggest that autophagy has a dual role in cancer and is dependent on biological factors such as the driving
oncogene, tumor suppressor involved and tumor type. Hence, autophagy is considered as a double-edged
sword, by both protecting from and promoting cancer [42,43] .

Autophagy acts as a tumor suppressor during tumorigenesis
Autophagy is widely documented as a tumor suppressive mechanism, as its deregulation leads to genomic
[44]
instability, aberrant mutations, tumor formation and metastasis . Primarily, the role of beclin1 in
autophagy has been studied extensively. For example, mice having monoallelic deletion of beclin1 gene
induce tumor formation. As is evident, the allelic loss of beclin1 was found in 40%-75% in breast, ovarian,
and prostate cancers [44,45] . It is well documented that Beclin-1 promotes autophagy by binding to Vps34 via its
conserved domain that was reported essential for tumor suppression. Recently, phosphorylation of multiple
tyrosine residues of beclin1 has also been observed, which leads to a decrease in the activity of beclin1/
[46]
PI3KC3 complex and thereby the reduction of autophagy .
The reduction of beclin1 protein levels is also reported in many brain cancers. A study conducted to
investigate beclin1 mRNA expression in different histotypes of brain tumors reported the expression levels
vary based on the type of tumor. After examining mRNA expression in 212 primary brain tumors, the study
identified low expression in most high-grade ependymal neoplasms, astrocytic and atypical meningiomas;
[47]
whereas, high expression in low-grade tumors and medulloblastomas . Additionally, monoallelic deletion/
mutations in UVRAG protein and decreased expression levels of Bif-1 were also reported in colon, gastric,
[38]
breast, prostate and bladder cancers . The reported results clearly indicate that autophagy related protein
Beclin-1 and its regulators (i.e., UVRAG and Bif-1) mediate tumor suppression.

Further, deregulation of several proteins of PI3K/Akt pathway were also reported to impair autophagy
mechanism and can lead to tumorigenesis. For example, phosphatase and tensin homolog protein was
reported to inhibit Akt survival pathway, and thereby induces autophagy mechanism. However, a mutation
in PTEN gene leads to constitutive activation of Akt and inhibition of autophagy, leading to cancer
formation [44,48] . Furthermore, the accumulations of p62 aggregates were reported to cause several cancers
[49]
owing to impaired autophagy mechanism. Another study by Kang et.al. , identified the frameshift
mutations with mononucleotide repeats in ATG genes in gastric and colorectal carcinomas. Further, this
study suggested that these mutations are associated with cancer progression by autophagy deregulation.
The study investigated the expression of BNIP3 (Bcl-2/adenovirus E1B 19 kDa-interacting protein), a key
regulator of mitochondrial autophagy in breast cancer and reported that BNIP3 expression is significantly
lost in invasive breast cancers and suggested that breast cancers cells shows high proliferation with low
BNIP3 expression. Thus, collectively these evidences suggest that autophagy plays essential role in tumor
suppression and conversely its deregulation leads to cancer.

Autophagy acts as a cell survival mechanism in cancer cells
Genome-wide screening studies show that many genes are involved in the regulation of autophagy either
[50]
through suppression or enhancement of autophagy . High throughput analyses also contribute to the
understanding of autophagy regulation at protein level and in terms of protein-protein interactions.
Further, research in yeast and animals suggests that stress-induced autophagy under nutrient-limiting
condition promotes cell survival by influencing the bioenergetics of the cell. A study conducted in human
prostate cancer cells PC3 and LNCaP, and breast cancer cells MCF7 shows that autophagy acts as a survival
mechanism in hypoxic tumor cells. Hypoxia inducible factor1, a positive regulator of autophagy enhances
[51]
tumor metabolism and metastasis , and thereby limits the radiation and chemotherapy. Hypoxia inducible
factor1 is involved in the induction of BNIP3 and BNIP3L which disrupts beclin1-bcl2 complex, and releases
beclin1 to induce autophagy. Further, BNIP3 induced autophagy acts as an adaptive survival mechanism in
[52]
hypoxia tumors . In vitro and in vivo studies also reported that autophagy acts as survival mechanism in
[3]
squamous cell carcinoma by protecting endoG-mediated apoptosis .