Mitochondrial Akt regulation of hypoxic tumor reprogramming

Cited 87 time in scopus
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Title
Mitochondrial Akt regulation of hypoxic tumor reprogramming
Author(s)
Y C Chae; V Vaira; M C Caino; H Y Tang; J H Seo; A V Kossenkov; L Ottobrini; C Martelli; G Lucignani; I Bertolini; M Locatelli; K G Bryant; J C Ghosh; S Lisanti; Bonsu Ku; S Bosari; L R Languino; D W Speicher; D C Altieri
Bibliographic Citation
Cancer Cell, vol. 30, no. 2, pp. 257-272
Publication Year
2016
Abstract
Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an “actionable” therapeutic target in cancer.
Keyword
AkthypoxiametabolismmitochondriaPDK1tumor cell proliferation
ISSN
1535-6108
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.ccell.2016.07.004
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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