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Hsp90 inhibitors, GA and 17AAG, lead to ER stress-induced apoptosis in rat histiocytoma

Aftab Taiyab, Amere S Sreedhar, Ch Mohan Rao
Biochemical Pharmacology 2009 July 15, 78 (2): 142-52
19464431
Heat shock protein 90 (Hsp90) is a major molecular chaperone that plays an essential role in the maintenance of several signaling molecules, most of which are oncogenic kinases. Hsp90 inhibition by specific inhibitors leads to destabilization and loss of activity of such proteins, thereby leading to inhibition of multiple signaling cascades. Due to this, Hsp90 has emerged as an important target for the treatment of cancer. Inhibition of Hsp90 has been reported to induce apoptosis in certain cancer cell types. However, the molecular details of induction of apoptosis upon Hsp90 inhibition are not understood. We have investigated the effect of Hsp90 inhibition on a non-adherent rat histiocytoma cell line, BC-8, using geldanamycin and 17-Allylamino-17-demethoxygeldanamycin. We show that Hsp90 inhibition induces ER stress, which leads to disruption of mitochondrial homeostasis, leading to apoptosis. Induction of ER stress leads to increased expression of ER chaperones, Grp78 and Grp94, cleavage of caspase-12 and increase in cytoplasmic calcium. We show that calcium and Bax are responsible for the decrease in mitochondrial membrane potential (Deltapsi(m)), thereby leading to the release of cytochrome c and activation of caspase-9. Moreover, calcium chelator and over-expression of Bcl-2 is able to confer protection against apoptosis upon Hsp90 inhibition. We conclude that inhibition of Hsp90 leads to ER stress-induced mitochondria-mediated apoptosis and that Bax and Ca(2+) play an important role in mitochondrial damage.

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