title: Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.
abstract: 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.
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Jessie Yanxiang
authors.initials: JY
authors.lastname: Guo
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Robin
authors.initials: R
authors.lastname: Mathew
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Strohecker
authors.forename: Gizem
authors.initials: G
authors.lastname: Karsli-Uzunbas
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
authors.forename: Guanghua
authors.initials: G
authors.lastname: Chen
authors.forename: Johanna M S
authors.initials: JM
authors.lastname: Lemons
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Karantza
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Coller
authors.forename: Robert S
authors.initials: RS
authors.lastname: Dipaola
authors.forename: Celine
authors.initials: C
authors.lastname: Gelinas
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Eileen
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D013217:Starvation