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Chaperoning tumour bioenergetics

Cancer cell growth and maintenance requires the ability to adapt and respond to multiple different environmental cues and stresses. Altieri and colleagues now report that heat shock protein 90 (HSP90), which regulates protein-folding quality control, also controls energy production and stress responses to promote tumour cell survival and growth (Cancer Cell 22, 331–344; 2012).

Using small-molecule inhibitors, the authors showed that the mitochondrial, but not the cytosolic, HSP90 pool regulates tumour cell bioenergetics by controlling the mitochondrial recruitment of hexokinase-II, a key glycolysis enzyme that also couples glucose metabolism to oxidative phosphorylation. They further demonstrated that HSP90 inhibition and impaired hexokinase-II activity deregulate key bioenergetic pathways by activating AMP-activated kinase (AMPK) and inhibiting mammalian target of rapamycin complex-1 (mTORC1). These signalling events were shown to promote tumour cell survival by inducing autophagy. HSP90 inhibition and the resulting mitochondrial proteotoxic stress and impaired bioenergetic responses also activated the unfolded protein response stress pathways in the endoplasmic reticulum, leading to tumour cell viability and proliferation. HSP90-controlled tumour bioenergetics promoted melanoma cell growth in vitro and prostate tumour growth in a genetic mouse model, and also correlated with negative outcome in lung cancer patients. These findings demonstrate that HSP90 integrates multiple pathways underlying energy production, survival and stress responses to provide a cytoprotective and proliferative advantage to tumour cells.

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Zaromytidou, AI. Chaperoning tumour bioenergetics. Nat Cell Biol 14, 1129 (2012). https://doi.org/10.1038/ncb2623

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