Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation.
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.
Department of Pathology, University of California, San Francisco Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
Rebecca
R
Lock
Srirupa
S
Roy
Candia M
CM
Kenific
Judy S
JS
Su
Eduardo
E
Salas
Sabrina M
SM
Ronen
Jayanta
J
Debnath
D000818:Animals; D023102:Anoikis; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071193:Autophagy-Related Protein 7; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006019:Glycolysis; D006801:Humans; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D025841:Small Ubiquitin-Related Modifier Proteins / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D044764:Ubiquitin-Activating Enzymes / Q000096:biosynthesis / Q000235:genetics; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; D019253:Proto-Oncogene Proteins c-bcl-2; D025841:Small Ubiquitin-Related Modifier Proteins; D018631:ras Proteins; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes