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Page 6 of 25 Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105

In aging process, the functional role of autophagy is expulsion of aggregated protein which increases the
lifespan; in the case of defective autophagy process, the formation of vacuoles and improper fusion of
[31]
vacuoles with the lysosomes results in impaired protein flux . In infectious disease, the functional role
of autophagy is to remove the bacterial and viral pathogens through sequestration in autophagic vacuoles
[32]
and then degradation. This provides immunity against pathogens ; while a defective autophagy process
provides a conducive environment for pathogens. In lysosomal storage disorders, the removal of lysosomal
stock such as fatty acids, cholesterol are defective and an increased number of autophagosomes and reduced
[33]
organelle turnover occur . In the case of neurodegeneration disorders, the neuronal protein aggregates are
removed by autophagic process; while, in the defective process the protein aggregates accumulate in neurons
[34]
leading to neurodegenaration .
Role of autophagy in cancer
Autophagy is a complex process that responds to a variety of stressful environments such as nutrient
deprivation, abnormal protein accumulation and damaged organelle, and thereby maintains the cellular
[35]
homeostasis . Autophagy plays a cyto-protective role by clearing the damaged organelles, misfolded
proteins and ROS, thus confining the genomic instability and aberrant mutations that ultimately leads to
cancer. Consequently, autophagy machinery can be defined as cell survival mechanism in normal and as
death mechanism in cancer cells.

However, deregulation of autophagy has been reported in a variety of diseases including cancer. Many
reports have shown that autophagy plays dual role in cancer development. In early stage of cancer, autophagy
suppresses/abolishes tumor formation by clearing the damaged proteins and organelles, and thereby induces
cell death; whereas in advanced cancers, the stress mediated properties of autophagy has been hijacked by
tumor cells to meet their increased metabolic requirements that are indispensable for tumor survival and rapid
proliferation. Hence, autophagy has been reported as a tumor promoter in advanced cancers. Additionally, the
regulation of autophagy through diverse signaling mechanisms can contribute upregulation/downregulation
of tumor suppressor/oncogenes, and that can lead to inhibition/induction of cancer development [36,37] . For
example, negative regulation of tumor suppressor genes through different signaling mechanisms (i.e., mTOR,
AMPK, etc.) could induce autophagy and suppression of cancer initiation; whereas, activation of oncogenes
could lead to inhibition of autophagy and promotion of cancer development.

It has been widely reported that autophagy modulates cancer growth and development, and this depends
on cancer type, stage, and genetic context. A basal level of autophagy is considered as a cancer suppressive
mechanism in normal cells. However, abnormal levels of autophagy in stressful conditions (i.e., Hypoxia,
ROS, etc.) lead to inhibition of break down of damaged organelles and proteins, and subsequent cancer
development. Nonetheless, it has been reported that mutation in autophagy related proteins leads to tumor
suppression/promotion in a variety of cancers. For example, BECN1 related proteins (e.g., BIF-1 etc.) have
been found abnormal/absent in gastric and colorectal cancer [38,39] . Further, mutation in UVRAG protein
[40]
reported to reduce autophagy, and consequent colorectal cancer development . On the other hand, an
unexpected high basal-level of autophagy has been reported in several types of RAS-activated cancers (e.g.,
[41]
pancreatic cancers) and inhibition of autophagy in these cancers hinders the tumor formation .

In order to identify alterations of different genes that are involved in autophagy signaling pathways, we have
analyzed 1,087 cancer patient samples data from Cbioportal database (http://www.cbioportal.org/). Through
this data analysis, we have noticed that mTOR gene shows high alterations with 12% (altered/profiled ratio =
128/1,087) and PIK3C3 shows 9% (altered/profiled ratio = 97/1,087) alterations. Further we also observed the
alterations of other genes including ULK1 (5%), UVRAG (5%), beclin1 (2.7%), ATG4B (4%), ATG16L1 (2.1%),
ATG5 (4%) and ATG12 (2.8%). Altogether, these studies explain that cell transformation and deregulation of
many signaling pathways are connected directly or indirectly with autophagy modulation. These evidences,