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Cancer Cell. 2012 Sep 11;22(3):331-44. doi: 10.1016/j.ccr.2012.07.015.

Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s.

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1
Prostate Cancer Discovery and Development Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.

Abstract

Tumors successfully adapt to constantly changing intra- and extracellular environments, but the wirings of this process are still largely elusive. Here, we show that heat-shock-protein-90-directed protein folding in mitochondria, but not cytosol, maintains energy production in tumor cells. Interference with this process activates a signaling network that involves phosphorylation of nutrient-sensing AMP-activated kinase, inhibition of rapamycin-sensitive mTOR complex 1, induction of autophagy, and expression of an endoplasmic reticulum unfolded protein response. This signaling network confers a survival and proliferative advantage to genetically disparate tumors, and correlates with worse outcome in lung cancer patients. Therefore, mitochondrial heat shock protein 90s are adaptive regulators of tumor bioenergetics and tractable targets for cancer therapy.

PMID:
22975376
PMCID:
PMC3615709
DOI:
10.1016/j.ccr.2012.07.015
[Indexed for MEDLINE]
Free PMC Article

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