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.
Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s / Y.C. Chae, M.C. Caino, S. Lisanti, J.C. Ghosh, T. Dohi, N.N. Danial, J. Villanueva, S. Ferrero Bogetto, V. Vaira, L. Santambrogio, S. Bosari, L.R. Languino, M. Herlyn, D.C. Altieri. - In: CANCER CELL. - ISSN 1535-6108. - 22:3(2012 Sep), pp. 331-344.
Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s
S. Ferrero Bogetto;V. Vaira;L. Santambrogio;S. Bosari;
2012
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.File | Dimensione | Formato | |
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