Inhibition of the mitochondrial Hsp90 chaperone network: a novel, efficient treatment strategy for cancer?

Research has shown that cancer cells exhibit multiple deregulated pathways, involving proliferation, migration and cell death. Heat-shock-proteins have evolved as "central regulators" and are implicated in the modulation of these pathways and in organelle-specific signaling. In this instance, heat-shock-proteins (Hsps) assist cancer cells in the maturation of proteins. Hsp90 is of particular interest because its enzymatic ATPase activity is elevated in malignant cells as compared to non-neoplastic counterparts. Consistent with its high-activity in cancer cells, Hsp90 stabilizes a considerable number of proteins being instrumental in carcinogenesis and the maintenance and growth of highly malignant cancers. Among its distribution Hsp90 is also localized within mitochondria of neoplastic cells of various origin, interacting with another chaperone, TRAP1 (Tumor necrosis factor type 1 receptor-associated protein or Heat-shock-protein 75) to antagonize the cell death promoting properties of the matrix protein, Cyclophilin-D. Several preclinical studies, including in vivo studies in both orthotopic and genetic animal models, have confirmed that targeting mitochondrial Hsp90 may be a novel efficient treatment method for highly recalcitrant tumors. This review summarizes the most recent findings of mitochondrial Hsp90 signaling and its potential implications for cancer therapy.