HSP90 regulates cell survival via inositol hexakisphosphate kinase-2.
Heat-shock proteins (HSPs) 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. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, 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.
Chakraborty
Anutosh
A
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Koldobskiy
Michael A
MA
Sixt
Katherine M
KM
Juluri
Krishna R
KR
Mustafa
Asif K
AK
Snowman
Adele M
AM
van Rossum
Damian B
DB
Patterson
Randen L
RL
Snyder
Solomon H
SH
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009675:Novobiocin / Q000494:pharmacology; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D009675:Novobiocin; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase; D002945:Cisplatin