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.

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming / Y. Chae, V. Vaira, M. Caino, H. Tang, J. Seo, A. Kossenkov, L. Ottobrini, C. Martelli, G. Lucignani, I. Bertolini, M. Locatelli, K. Bryant, J. Ghosh, S. Lisanti, B. Ku, S. Bosari, L. Languino, D. Speicher, D. Altieri. - In: CANCER CELL. - ISSN 1535-6108. - 30:2(2016 Aug 08), pp. 257-272. [10.1016/j.ccell.2016.07.004]

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

V. Vaira
Secondo
;
L. Ottobrini;C. Martelli;G. Lucignani;I. Bertolini;M. Locatelli;S. Bosari;
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.
Akt; hypoxia; metabolism; mitochondria; PDK1; tumor cell proliferation
Settore MED/36 - Diagnostica per Immagini e Radioterapia
Settore MED/50 - Scienze Tecniche Mediche Applicate
Settore MED/04 - Patologia Generale
8-ago-2016
Article (author)
File in questo prodotto:
File Dimensione Formato  
cancer cell 2016 1-s2.0-S153561081630335X-main.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 6.63 MB
Formato Adobe PDF
6.63 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/453840
Citazioni
  • ???jsp.display-item.citation.pmc??? 62
  • Scopus 155
  • ???jsp.display-item.citation.isi??? 154
social impact