Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.

By J. Y. Guo, Hsin-Yi Chen, Robin Mathew, Jing Fan, A. Strohecker, G. Karsli-Uzunbas, Jurre J. Kamphorst, Guanghua Chen, Johanna M. S. Lemons, V. Karantza and 5 more. Genes & Development, 2011

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Autophagy is a catabolic pathway used by cells to support metabolism in response to starvation and to clear damaged proteins and organelles in response to stress. We report here that expression of a H-ras(V12) or K-ras(V12) oncogene up-regulates basal autophagy, which is required for tumor cell survival in starvation and in tumorigenesis. In Ras-expressing cells, defective autophagosome formation or cargo delivery causes accumulation of abnormal mitochondria and reduced oxygen consumption. Autophagy defects also lead to tricarboxylic acid (TCA) cycle metabolite and energy depletion in starvation. As mitochondria sustain viability of Ras-expressing cells in starvation, autophagy is required to maintain the pool of functional mitochondria necessary to support growth of Ras-driven tumors. Human cancer cell lines bearing activating mutations in Ras commonly have high levels of basal autophagy, and, in a subset of these, down-regulating the expression of essential autophagy proteins impaired cell growth. As cancers with Ras mutations have a poor prognosis, this "autophagy addiction" suggests that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat these aggressive cancers.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3b64fdc3e84ea13bc641c81acb09280c8ee4ac7c

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Citations in the corpus

From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates (2015, background): “For example, ATG5-deficient immortal, nontumorigenic baby mouse kidney epithelial cells display no growth defects when cultured under normal media conditions; however, when such cells are placed into starvation media, they undergo apoptosis at a greatly accelerated rate compared with controls (Guo e”
The Roles of Autophagy in Cancer (2018, background): “the development of some deadly cancers, including lung, colon, and pancreatic [82,83,84,85].”
Pancreatic cancers require autophagy for tumor growth. (2011, positive): “In this regard, our data are consistent with recent work from White and colleagues (Guo et al. 2011) showing that transformation by oncogenic RAS may cause an addiction to autophagy to maintain energy balance.”
Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development (2013, background): “It has been shown that autophagy allows Rastransformed cells to maintain their energy supply during nutrient starvation and tumorigenesis (Guo et al., 2011).”
KRAS: feeding pancreatic cancer proliferation (2014, positive): “Similar analyses in the pancreatic cancer cell line PANC-1 and other RAS mutant human tumor cell lines showed that high basal autophagy is necessary for the growth and survival of these cell lines [62].”
The Role of Autophagy in Cancer: Therapeutic Implications (2011, background): “Recent data indicate that human cancer cell lines bearing activating mutations inH-ras or K-ras have high basal levels of autophagy even in the presence of abundant nutrients (32).”