Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis

Guo, Jessie Yanxiang; Chen, Hsin Yi; Mathew, Robin; Fan, Jianqing; Strohecker, Anne M.; Karsli-Uzunbas, Gizem; Kamphorst, Jurre J.; Chen, Guanghua; Lemons, Johanna M. S.; Karantza, Vassiliki; Coller, Hilary A.; DiPaola, Robert S.; Gélinas, Céline; Rabinowitz, Joshua D.; White, Eileen

doi:10.1101/gad.2016311

Cited by 1,155 publications

(1,190 citation statements)

References 34 publications

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“…These latter cells have a high basal autophagy rate, helping them to survive metabolic hardship 6,7 . The previous observation 8 that PDAC-cell scavenging of extracellular proteins such as albumin can support PDAC metabolism and growth in nutrient-limited conditions highlights the tendency of these cancer cells to exploit diverse nutrient sources.…”

Section: Jurre J Kamphorst and Eyal Gottliebmentioning

confidence: 99%

Friendly neighbours feed tumour cells

Kamphorst

Gottlieb

2016

Nature

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Section: Jurre J Kamphorst and Eyal Gottliebmentioning

confidence: 99%

Friendly neighbours feed tumour cells

Kamphorst

Gottlieb

2016

Nature

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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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“…The dependence of K-Ras-mutated cells on glucose partially results from the need for increased carbon flux through the pentose phosphate pathway . Although previous work showed suppression of autophagy with expression of mutant K-Ras (Furuta et al, 2004), a number of recent studies have illustrated the ability of mutant K-Ras to promote basal autophagy (Guo et al, 2011;Kim et al, 2011b;Lock et al, 2011). In these studies, suppression of autophagy limited the ability of mutant K-Ras to promote anchorage-independent growth in vitro and tumorigenesis in vivo.…”

Section: Effects Of Metabolic Reprogramming On Autophagy: Glycolysismentioning

confidence: 97%

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

Eng

Abraham

2011

Oncogene

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Tumorigenesis is often accompanied by metabolic changes that favor rapid energy production and increased biosynthetic capabilities. These metabolic adaptations promote the survival and proliferation of tumor cells, and in conjunction with the hypoxic and metabolically challenged tumor microenvironment, influence autophagic activity. Autophagy is a catabolic process that allows cellular macromolecules to be broken down and re-utilized as metabolic precursors. Stimulation of autophagy promotes the survival of tumor cells under stressful metabolic and environmental conditions, and counters the potentially deleterious effects of mitochondrial dysfunction and the ROS that these organelles generate. However, inhibition of autophagy has also been reported to fuel tumorigenesis. In spite of the advances in our understanding of the relationship between autophagy and tumorigenesis, it remains unclear whether the therapeutic approaches targeting autophagy should aim to increase or decrease autophagic flux in tumor tissues in human patients. Here, we review how metabolic reprogramming influences autophagic activity in tumors, and discuss how inhibition of autophagy might be exploited to target tumor cells that show altered metabolism.

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Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis

Cited by 1,155 publications

References 34 publications

Friendly neighbours feed tumour cells

Friendly neighbours feed tumour cells

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

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

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