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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    ABSTRACT: j.celrep.2014.06.061 This is an open access article under the CC BY-NC-ND license ( SUMMARY Reprogramming of metabolic pathways contributes to human disease, especially cancer, but the regula-tors of this process are unknown. Here, we have generated a mouse knockout for the mitochondrial chaperone TRAP-1, a regulator of bioenergetics in tumors. TRAP-1 À/À mice are viable and showed reduced incidence of age-associated pathologies, including obesity, inflammatory tissue degenera-tion, dysplasia, and spontaneous tumor formation. This was accompanied by global upregulation of oxidative phosphorylation and glycolysis transcrip-tomes, causing deregulated mitochondrial respira-tion, oxidative stress, impaired cell proliferation, and a switch to glycolytic metabolism in vivo. These data identify TRAP-1 as a central regulator of mito-chondrial bioenergetics, and this pathway could contribute to metabolic rewiring in tumors. INTRODUCTION
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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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    ABSTRACT: Mitochondrially-bound hexokinase II (mtHKII) has long been known to confer cancer cells with their resilience against cell death. More recently, mtHKII has emerged as a powerful protector against cardiac cell death. mtHKII protects against IR injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end-effectors through which ischemic preconditioning protects against myocardial ischemia-reperfusion injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated OMM permeability during ischemia and reperfusion resulting in stabilisation of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced ROS production. Increasing mtHK may also have important metabolic consequences, such as improvement of glucose-induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of HKII may contribute to the altered sensitivity of diabetes to cardiac ischemic diseases. The interaction of HKII with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge is now to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischemic preconditioning, metformin administration and miR-155/miR-144 manipulations are potential means of doing just that.
    British Journal of Pharmacology 08/2013; 171(8). DOI:10.1111/bph.12363 · 4.99 Impact Factor
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    ABSTRACT: Although essential for energy production and cell fate decisions, the mechanisms that govern protein homeostasis, or proteostasis, in mitochondria are only recently beginning to emerge. Fresh experimental evidence has uncovered a role of molecular chaperones of the heat shock protein 90 (Hsp90) family in overseeing the protein folding environment in mitochondria. Initially implicated in protection against cell death, there is now evidence that Hsp90-directed protein quality control in mitochondria connects to hosts of cellular homeostatic networks that become prominently exploited in human cancer.
    Cellular and Molecular Life Sciences CMLS 09/2012; 70(14). DOI:10.1007/s00018-012-1177-0 · 5.86 Impact Factor
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