INHIBITION OF K-RAS-TRANSFORMED RODENT AND HUMAN CANCER CELL-GROWTH VIA INDUCTION OF APOPTOSIS BY IRREVERSIBLE INHIBITORS OF RAS ENDOPROTEASE

Proteolytic removal of the carboxyl terminal tripeptide of Ras oncopro teins is important in the Ras function. Two chloromethyl ketones, BFCC MK and UM96001, designed to be the Ras C-terminal sequence-specific en doprotease inhibitors, at low micromolar concentrations (5.0 mu M), po tently inhibit the growth of ras-transformed rodent and human cancer c ells, whereas untransformed NIH/3T3 cells are not affected under the s ame conditions. Furthermore, BFCCMK and UM96001 block more than 98% of the anchorage-independent clonogenic growth of ras-transformed rat an d human cancer cells at low micromolar concentrations. The blocking of cancer cell growth may be due to the selective induction of apoptosis of ras-transformed cells by these inhibitors. These results provide t he first experimental evidence that the endoproteolysis of Ras oncopro teins is important for the growth and apoptosis of ras-transformed can cer cells. Therefore, the Ras C-terminal sequence-specific endoproteas e may be a potential new target for the treatment of human cancers ind uced by ras mutations. (C) 1998 Elsevier Science Ireland Ltd. All righ ts reserved.