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Control of Tumor Bioenergetics and Survival Stress Signaling by Mitochondrial HSP90s

Prostate Cancer Discovery and Development Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Cancer cell (Impact Factor: 23.89). 09/2012; 22(3):331-44. DOI: 10.1016/j.ccr.2012.07.015
Source: PubMed

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.

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    • "The data presented here refute recent and contradictory claims that TRAP-1 inhibits mitochondrial SDHB-complex II activity (Sciacovelli et al., 2013), or, conversely, promotes glycolysis (Yoshida et al., 2013). These preliminary suggestions were at odd with a large body of literature, in which pharmacologic or genetic targeting of TRAP-1 inhibited mitochondrial respiration (Butler et al., 2012; Chae et al., 2013), impaired mitochondrial quality control (Costa et al., 2013), caused oxidative damage (Butler et al., 2012; Pridgeon et al., 2007), and suppressed ATP production (Agorreta et al., 2014; Chae et al., 2012). Consistent with this model, we found that homozygous deletion of TRAP-1 resulted in decreased SDHB expression, reflecting loss of protein-folding quality control in mitochondria (Chae et al., 2013). "
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    • "HKII has recently shown to be released from mitochondria in tumour cells during inhibition of mitochondrial HSP90 (Chae et al., 2012). HSP90 has previously been demonstrated to have cardioprotective capacity (Latchman et al, 2001; Xiang et al., 2010) and the mitochondrial heat shock protein, tumour necrosis factor receptor-associated protein 1 (TRAP1), is known to be present in the heart (Xiang et al., 2010). "
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