Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 20, Pages E1839-E1848Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1208530110
Keywords
oncogene; cell death; cancer metabolism
Categories
Funding
- Academy of Finland
- Finnish Funding Agency for Technology and Innovation (TEKES)
- Sigrid Juselius Foundation
- Finnish Cancer Organizations
- Biomedicum Foundation
- Emil Aaltonen Foundation
- Ida Montini Foundation
- Orion-Farmos Research Foundation
- Paulo Foundation
- University of Helsinki
- Innovative Medicines Initiative [115188]
- European Union
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Oncogenic transcription factor Myc deregulates the cell cycle and simultaneously reprograms cellular metabolism to meet the biosynthetic and bioenergetic needs of proliferation. Myc also sensitizes cells to mitochondria-dependent apoptosis. Although metabolic reprogramming has been circumstantially connected to vulnerability to apoptosis, the connecting molecular pathways have remained poorly defined. Here, we show that Myc-induced altered glutamine metabolism involves ATP depletion and activation of the energy sensor AMP-activated protein kinase (AMPK), which induces stabilizing phosphorylation of p53 at Ser15. Under influence of Myc, AMPK-stabilized tumor suppressor protein p53 accumulates in the mitochondria and interacts with the protein complex comprised of B-cell lymphoma 2 (Bcl-2) antagonist/killer (BAK) and Bcl2-like 1 (Bcl-xL). Mitochondrial p53 induces conformational activation of proapoptotic Bak without disrupting the Bak-Bcl-x(L) interaction. Further liberation of Bak specifically from the p53-activated Bak-Bcl-x(L) complex leads to spontaneous oligomerization of Bak and apoptosis. Thus, Myc-induced metabolic changes are coupled via AMPK and phospho-p53 to the mitochondrial apoptosis effector Bak, demonstrating a cell-intrinsic mechanism to counteract uncontrolled proliferation.
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