Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation

Lock, Rebecca; Roy, Srirupa; Kenific, Candia M.; Su, Judy S.; Salas, Eduardo; Ronen, Sabrina M.; Debnath, Jayanta

doi:10.1091/mbc.e10-06-0500

Cited by 414 publications

(396 citation statements)

References 34 publications

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“…18 Given that recent studies have demonstrated that oncogenic H-Ras or K-Ras promotes basal autophagy as a mechanism to promote tumor cell survival, [19][20][21][22] we assessed if EcdCRas promote cell survival under nutrient deprivation by elevating autophagy markers.…”

Section: Ecd Plus Ras Overexpression Induces Upregulation Of Autophagmentioning

confidence: 99%

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

et al. 2015

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Section: Ecd Plus Ras Overexpression Induces Upregulation Of Autophagmentioning

confidence: 99%

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

et al. 2015

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“…11 It has also been shown that in cells expressing oncogenic Ras, autophagy is required to promote tumorigenesis by maintaining oxidative metabolism or facilitating glycolysis. 12,13 Moreover, it has also been demonstrated that the suppression of autophagy by the expression of FIP200, a component of the ULK1-Atg13-FIP200-Atg101 complex that is essential for the induction of autophagy, could suppress mammary tumorigenesis induced by the polyomavirus middle T antigen in mice. 14 These observations indicated a protumorigenic role of autophagy.…”

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confidence: 99%

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

et al. 2014

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The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC. Autophagy (i.e., macroautophagy) is important for cells to remove protein aggregates and damaged organelles. Its dysfunction can cause a variety of diseases including cancers. 1,2 However, its role in carcinogenesis is apparently complex, as it has been shown in different reports to positively or negatively regulate carcinogenesis. 3,4 Autophagy apparently can function as a tumor suppressor, as the gene encoding Beclin-1, a component of the phosphatidylinositol-3-kinase class III (PI3KC3) complex that is essential for the initiation of autophagy, is often monoallelically deleted or mutated in breast, ovarian and prostate cancers. 5 Frameshift mutations in Atg2B, Atg5, Atg9B and Atg12 autophagy genes are also often found in gastric and colorectal cancers with microsatellite instability. 6 The tumor suppressor role of autophagy is further supported by the studies using mouse models. It has been shown that the monoallelic deletion of the Beclin-1 gene in mice induced tumor lesions in various tissues, 7 Atg4C-knockout (KO) mice had increased susceptibility to carcinogens for the development of fibrosarcomas 8 and the systemic mosaic KO of Atg5 and the liver-specific KO of Atg7 in mice led to the development of benign liver adenomas. 9,10 Autophagy has also been shown to promote tumor growth. It has been shown that autophagy can enhance the survival of tumor cells in the hypoxic regions of solid tumors. 11 It has also been shown that in cells expressing oncogenic Ras, autophagy is required to promote tumorigenesis by maintaining oxidative metabolism or facilitating glycolysis. 12,13 Moreover, it has also been demonstrate...

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“…55 Inhibition of autophagy in Ras-expressing cells leads to decreased cell proliferation, transformation and failure of tumor formation in mice. [59][60][61] Contrary to this, other studies have shown an anticancer role by enhancing autophagy. 47,52,62,63 Table 1 provides a list of miRNAs reported with therapeutic potential for treating cancer.…”

Section: Therapeutic Potential Of Mirnas and Autophagic Pathwaymentioning

confidence: 85%