Research on tumor-suppressive activity of apoptosis-related cysteine proteinase ICH-1

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Although it is generally accepted that caspase family proteases play central roles in induction of apoptosis, their other biological activity remains to be proved. Therefore, we have transfected cDNAs of caspase-1 (ICE), 2 (ICH-1) and 3 (CPP32) into Ha-ras-transformed NIH3T3 cells and investigated the effects after induction of their expression. High expression of these proteases alone did not result in apoptosis-like cell death. However, morphological reversion was frequently observed in clones which overexpressed caspase-2. The reversion was well correlated to the expression level of caspase-2. Moreover, the reverted clones lost the ability of anchorage-independent growth in soft agar medium. These results suggest that caspase-2 possesses the tumor suppressive activity toward Ha-ras-transformed cells. Similar effects of caspase-2 were also observed for v-src-transformed NIH3T3 cells but not for Ki-ras-transformed cells. Thus, caspase-2 may affect a signal transduction pathway which is specific for Src and Ha-Ras. Further western blot analysis showed that the expression level of Ha-Ras was reduced in caspase-2-producing cells. In vitro incubation of cell extract of Ha-ras-transformed cells resulted in degradation of Ha-Ras protein. Th is degradation was completely suppressed in the presence of caspase inhibitors. Taken together, it is plausible that caspase-2 induced reversion of transformed cells by stimulating the degradation of Ha-Ras protein.