Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Cancer cells activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation.
Autophagy functions as a tumor suppression mechanism by removing damaged organelles/proteins and limiting cell growth and genomic instability. Beclin 1 is a protein required for autophagy signaling. and Beclin 1+/- mice were shown to be tumor prone, indicating that Beclin 1 is a haploinsufficient cancer suppressor gene. However, overexpression of Beclin 1 can inhibit cancer development.
Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of cancer cells. Thus these experiments show autophagy’s role as a tumor suppressor.
Evidence indicates that the predominant role of autophagy in cancer cells is to confer stress tolerance, which serves to maintain cancer cell survival. Knockdown of essential autophagy genes in cancer cells has been shown to confer or potentiate the induction of cell death.
Cancer cells have high metabolic demands due to increased cellular proliferation, and studies have shown in vivo models, exposure to metabolic stress can impair survival in autophagy-deficient cells compared with autophagy-proficient cells.
Cytotoxic and metabolic stresses, including hypoxia and nutrient deprivation, can activate autophagy for recycling of ATP and to maintain cellular biosynthesis and survival by continuous cellular energy production. These indicates that block the crucial components in autophagy siagnaling may be an effective treatment approach of cancer.
Conversely, the inhibition of autophagy in cancer cells was shown to delay the senescence phenotype. A subset of Atgs (ULK1 and ULK3) is upregulated during senescence, and overexpression of ULK3 was shown to induce Autophagy and senescence.
Autophagy has been shown to mediate Ras oncogene-induced senescence. Cellular senescence represents a state of cell cycle arrest maintained by the expression of cell cycle inhibitors (p16Ink4a, p21Cip1, and p27Kip1) in metabolically viable cells. The senescence phenotype can be induced by oncogenes, DNAdamaging drugs, or oxidative stress, and their ability to induce senescence is enhanced by functional p53 and Rb tumor suppressor genes. Senescence has been suggested as a mechanism for autophagy-mediated tumor dormancy.
Autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. Autophagy is more important for some tumor cells than for others. This idea has been called “autophagy addiction” and identifies autophagy as a novel therapeutic target for some tumors.
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