INDUCTION OF HYDROGEN-PEROXIDE PRODUCTION AND BAX EXPRESSION BY CASPASE-3(-LIKE) PROTEASES IN TYROSINE KINASE INHIBITOR-INDUCED APOPTOSIS IN HUMAN SMALL-CELL LUNG-CARCINOMA CELLS

In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978 -4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as er bstatin and herbimycin A, was mediated by H2O2 via a newly synthesized protein(s). In the present study, we demonstrated that induction of a poptosis by erbstatin resulted in activation of caspase-3(-like) prote ases, which are interleukin-1 beta-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced th e extent of cell death and H2O2 generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin, Erbstati n-induced Bax expression was inhibited by the inhibitor of caspase-3(- like) proteases. These results indicate that generation of intracellul ar H2O2 and Bax expression in tyrosine kinase inhibitor-induced apopto sis were modulated by the activation of caspase-3(-like) proteases in SCLC cells. (C) 1998 Academic Press.