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Drug‐induced Myc‐mediated apoptosis of cancer cells is inhibited by stress protein Hsp70
Author(s) -
Afanasyeva Elena A.,
Komarova Elena Yu.,
Larsson LarsGunnar,
Bahram Fuad,
Margulis Boris A.,
Guzhova Irina V.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22974
Subject(s) - apoptosis , hsp70 , cytochrome c , caspase , biology , ectopic expression , caspase 9 , effector , microbiology and biotechnology , cancer research , gene knockdown , caspase 3 , heat shock protein , chemistry , cell culture , programmed cell death , biochemistry , genetics , gene
The Myc oncoprotein serves a dual function by stimulating cells both towards growth and apoptosis. The latter functions are often abrogated during tumor development. The Hsp70 stress protein is a potent anti‐apoptotic molecule, but its potential role in protecting cells from Myc‐mediated apoptosis has not been investigated. Our results show that activated Myc potentiated apoptosis induced by the cancer drugs etoposide (ETO) and camptothecin (CAMP) in v‐Myc‐expressing human U‐937 monoblastic cells and in Rat1 cells containing a conditionally active Myc/estrogen receptor (MycER) fusion protein. However, both heat shock and ectopic Hsp70 expression protected the cells from Myc‐mediated apoptosis after drug treatment in both systems. The increased susceptibility to the anti‐tumor drugs by activated Myc was enhanced by siRNA‐mediated knockdown of Hsp70 expression in U‐937 cells. Addressing the mechanisms by which Myc and Hsp70 promotes and inhibits drug‐induced apoptosis, respectively, we found that v‐Myc stimulated cytochrome c release and activation of effector caspase‐9, ‐3 and ‐7, but not of initiator caspase‐8. Inhibition of caspase‐9 specifically reduced v‐Myc‐stimulated apoptosis, whereas inhibition of caspase‐8 and ‐3/7 reduced apoptosis both in v‐myc‐expressing and parental ETO‐treated U‐937 cells. Interestingly, Myc‐stimulated activation of effector caspases was inhibited, but cytochrome c release was not affected by Hsp70 expression, suggesting that Hsp70 interferes with the proapoptotic function of Myc downstream of mitochondria, at the level of caspase‐9 and downstream caspases. In conclusion, Hsp70 seems to have key function in inhibition of apoptosis mediated by Myc and may therefore play an important role in Myc‐driven oncogenesis. © 2007 Wiley‐Liss, Inc.