HSP90 regulates cell survival via inositol hexakisphosphate kinase-2.

Heat-shock proteins (HSP5) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. lnositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate 1P7 [diphosphoinositol pentakisphosphate (5-PP-IP5)]. mediates apoptosis. Increased 1P6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds 1P6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-1P6K2 binding elicit activation of 1P6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy. [ABSTRACT FROM AUTHOR]