Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation
Rebecca Lock,Srirupa Roy,Candia M. Kenific,Judy S. Su,Eduardo Salas,Sabrina M. Ronen,Jayanta Debnath +6 more
TLDR
This study demonstrates an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent growth driven by a strong oncogenic insult—mutationally active Ras.Abstract:
The protumorigenic functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to diverse stresses. Here we demonstrate an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent transformation driven by a strong oncogenic insult—mutationally active Ras. In cells ectopically expressing oncogenic H-Ras as well as human cancer cell lines harboring endogenous K-Ras mutations, autophagy is induced following extracellular matrix detachment. Inhibiting autophagy due to the genetic deletion or RNA interference–mediated depletion of multiple autophagy regulators attenuates Ras-mediated adhesion-independent transformation and proliferation as well as reduces glycolytic capacity. Furthermore, in contrast to autophagy-competent cells, both proliferation and transformation in autophagy-deficient cells expressing oncogenic Ras are insensitive to reductions in glucose availability. Overall, increased glycolysis in autophagy-competent cells facilitates Ras-mediated adhesion-independent transformation, suggesting a unique mechanism by which autophagy may promote Ras-driven tumor growth in specific metabolic contexts.read more
Citations
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Self-consumption: the interplay of autophagy and apoptosis
TL;DR: The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens, and the disruption of the relationship between autphagy and apoptosis has important pathophysiological consequences.
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Targeting autophagy in cancer
TL;DR: A way forward is suggested for the effective targeting of autophagy by understanding the context-dependent roles of autophile and by capitalizing on modern approaches to clinical trial design.
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RAS oncogenes: weaving a tumorigenic web
TL;DR: This Review describes how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.
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Drugging the undruggable Ras: mission possible?
TL;DR: This Review summarizes the progress and the promise of five key approaches for the development of RAS-inhibitory molecules and addresses the issue of whether blocking RAS membrane association is a viable approach.
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Deconvoluting the context-dependent role for autophagy in cancer
TL;DR: In this article, the authors define the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autoophagy-based therapeutic intervention, which can be either tumour suppressive or tumour promoting.
References
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