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GSK3 promotes arsenite‐induced apoptosis via facilitation of mitochondria disruption
Author(s) -
Watcharasit Piyajit,
Thiantanawat Apinya,
Satayavivad Jutamaad
Publication year - 2008
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1296
Subject(s) - apoptosis , poly adp ribose polymerase , arsenite , gsk 3 , mitochondrion , microbiology and biotechnology , biology , cytochrome c , signal transduction , kinase , programmed cell death , chemistry , biochemistry , enzyme , polymerase , arsenic , organic chemistry
Arsenic is an environmental toxicant that recently has been shown to have anticancer activity against a number of types of cancer cells by inducing apoptosis. Glycogen synthase kinase‐3 (GSK3), a serine/threonine kinase, is an important pro‐apoptotic signaling enzyme. Although GSK3 has been shown to promote apoptosis caused by a wide variety of insults, a role for GSK3 in arsenic‐induced apoptosis has not yet been identified. Investigation of the involvement of GSK3 in arsenite‐induced apoptosis demonstrated that arsenite induced apoptosis in SH‐SY5Y human neuroblastoma cells, activating the executioner caspase‐3 which caused cleavage of poly‐ADP ribose‐polymerase (PARP). Two selective GSK3 inhibitors, lithium and SB216763, attenuated caspase‐3 activation and PARP cleavage induced by arsenite treatment indicating that GSK3 contributed to arsenite‐induced apoptosis. Apoptotic signaling following exposure to arsenite involved cytochrome C release from mitochondria, and this was reduced by inhibition of GSK3 indicating that GSK3 promotes arsenite‐induced apoptotic signaling upstream of mitochondrial disruption. Moreover, arsenite induced the translocation of Bax and p53 to the mitochondria and the activation‐associated oligomerization of Bax, and these crucial events were reduced by inhibition of GSK3, indicating that GSK3 promotes arsenite‐induced apoptosis by facilitating signals leading to mitochondrial apoptotic events. Taken together, the findings from this study reveal that GSK3 promotes arsenite‐induced apoptosis by facilitating signaling leading to disruption of mitochondria. Copyright © 2007 John Wiley & Sons, Ltd.