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. 2012 Nov 21;2:171.
doi: 10.3389/fonc.2012.00171. eCollection 2012.

The Interplay Between Autophagy and ROS in Tumorigenesis

Free PMC article

The Interplay Between Autophagy and ROS in Tumorigenesis

Sameera Kongara et al. Front Oncol. .
Free PMC article


Reactive oxygen species (ROS) at physiological levels are important cell signaling molecules. However, aberrantly high ROS are intimately associated with disease and commonly observed in cancer. Mitochondria are primary sources of intracellular ROS, and their maintenance is essential to cellular health. Autophagy, an evolutionarily conserved process whereby cytoplasmic components are delivered to lysosomes for degradation, is responsible for mitochondrial turnover and removal of damaged mitochondria. Impaired autophagy is implicated in many pathological conditions, including neurological disorders, inflammatory bowel disease, diabetes, aging, and cancer. The first reports connecting autophagy to cancer showed that allelic loss of the essential autophagy gene BECLIN1 (BECN1) is prevalent in human breast, ovarian, and prostate cancers and that Becn1(+) (/) (-) mice develop mammary gland hyperplasias, lymphomas, lung and liver tumors. Subsequent studies demonstrated that Atg5(-/-) and Atg7(-/-) livers give rise to adenomas, Atg4C(-/-) mice are susceptible to chemical carcinogenesis, and Bif1(-/-) mice are prone to spontaneous tumors, indicating that autophagy defects promote tumorigenesis. Due to defective mitophagy, autophagy-deficient cells accumulate damaged mitochondria and deregulated ROS levels, which likely contribute to their tumor-initiating capacity. However, the role of autophagy in tumorigenesis is complex, as more recent work also revealed tumor dependence on autophagy: autophagy-competent mutant-Ras-expressing cells form tumors more efficiently than their autophagy-deficient counterparts; similarly, FIP200 deficiency suppresses PyMT-driven mammary tumorigenesis. These latter findings are attributed to the fact that tumors driven by powerful oncogenes have high metabolic demands catered to by autophagy. In this review, we discuss the relationship between ROS and autophagy and summarize our current knowledge on their functional interactions in tumorigenesis.

Keywords: ROS; autophagy; cancer; inflammation; oxidative stress; p62.


Reactive oxygen species-mediated autophagy regulation. The ULK1/2–FIP200–mAtg13 and Beclin1–Vps34–p150 protein complexes together with the two ubiquitin-like proteins Atg12 and LC3 (or Atg8) and their conjugating proteins, including Atg7 (E1-like enzyme), Atg10 (E2-like enzyme), and Atg3 (E2-like enzyme), are the primary regulators of autophagosome formation and, thus, autophagy induction. Atg4 cleaves Pro-LC3 at its C-terminal-end, Atg7 and Atg3 add phosphatidyl ethanolamine (PE), and LC3-PE is then incorporated into the autophagosome membrane; Atg4 can also cleave LC3-PE to release free LC3 and negatively impact autophagy. The PI3K–Akt–mTORC1 pathway suppresses autophagy by inhibiting the ULK1/2–FIP200–mAtg13 complex. PI3K is activated in response to hormones and growth factors and suppresses TSC1/2 activity, thus resulting in Akt and mTORC1 activation; the phosphatase PTEN antagonizes PI3K, while the peroxiredoxins Prdx1 and 2 maintain PTEN function by preventing its oxidation. mTORC1 is also negatively regulated by HIF-1α via BNIP3 induction and by ATM via LKB1 and AMPK. The Beclin1–Vps34–p150 complex is positively regulated by Bif-1, UVRAG, AMBRA, and HMGB1, and negatively regulated by Bcl-2 and RUBICON. ROS stimulate autophagy by activating HIF-1α, AMPK, ATM, HMGB1, JNK1, ERK1/2 and inhibiting the PE-cleaving activity of Atg4, without affecting its ability to process the C-terminal end of LC3. ROS inhibit PTEN and are hypothesized to negatively affect TSC1/2 activity, potentially inhibiting autophagy. Upon its induction, autophagy results in ROS suppression.
Interplay between ROS and autophagy in tumorigenesis. Autophagy is induced by ROS and functions to mitigate oxidative stress. Defective autophagy leads to ROS accumulation and mitochondrial damage; in turn, malfunctioning mitochondria become additional sources of ROS, thereby creating a vicious cycle. While moderately high ROS levels are mutagenic and likely mediate tumor initiation in association with autophagy defects, very high ROS levels may result in apoptosis, and, thus, inhibit both tumor initiation and progression.

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