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: 23.52). 09/2012; 22(3):331-44. DOI: 10.1016/j.ccr.2012.07.015
Source: PubMed


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
    Cell Reports 07/2014; DOI:10.1016/j.celrep.2014.06.061 · 8.36 Impact Factor
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    • "Both gamitrinib [15,16] and DOX [38,39] have previously been shown to activate JNK and CHOP signaling pathways. Turning on these stress pathways activates the proapoptotic Bcl-2 family protein Bim through elevated gene expression and/or phosphorylation, leading to mitochondrial cell death [40,41]. "
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    ABSTRACT: Background A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy. Methods The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration. Results Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity. Conclusions The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.
    BMC Cancer 06/2014; 14(1):431. DOI:10.1186/1471-2407-14-431 · 3.36 Impact Factor
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    • "Impaired mitochondrial function [16] (Figure 4A, TMRM staining) and slightly elevated cytoplasmic calcium (Figure 4A, Fluo-4 staining) were frequently found in gamitrinib-treated cells, even at non-toxic dose of the drug. Therefore, we hypothesized that calcium-mediated stress propagation can render cells sensitive to additional stresses, i.e. lowering the cell death threshold. "
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    ABSTRACT: Background Resistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics. Mitochondria and the endoplasmic reticulum (ER) are physically interconnected organelles that can sense and exchange various stress signals. Although there have been many studies on stress propagation from the ER to mitochondria, reverse stress signals originating from mitochondria have not been well reported. Methods After inactivation of the proteins by pharmacologic and genetic methods, the signal pathways were analyzed by fluorescence microscopy, flow cytometry, MTT assay, and western blotting. A mouse xenograft model was used to examine synergistic anticancer activity and the action mechanism of drugs in vivo. Results We show in this study that mitochondrial heat shock protein 90 (Hsp90) suppresses mitochondria-initiated calcium-mediated stress signals propagating into the ER in cancer cells. Mitochondrial Hsp90 inhibition triggers the calcium signal by opening the mitochondrial permeability transition pore and, in turn, the ER ryanodine receptor, via calcium-induced calcium release. Subsequent depletion of ER calcium activates unfolded protein responses in the ER lumen, thereby increasing the expression of a pro-apoptotic transcription factor, CEBP homologous protein (CHOP). Combined treatment with the ER stressor thapsigargin and the mitochondrial Hsp90 inhibitor gamitrinib augmented interorganelle stress signaling by elevating CHOP expression, and showed synergistic cytotoxic activity exclusively in cancer cells in vitro and in vivo. Conclusions Collectively, mitochondrial Hsp90s confer cell death resistance to cancer cells by suppressing the mitochondria-initiated calcium-mediated interorganelle stress response.
    Molecular Cancer 06/2014; 13(1):148. DOI:10.1186/1476-4598-13-148 · 4.26 Impact Factor
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