RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage

The-effect of neoplastic transformation on the response to genotoxic stress is of significant clinical interest. In this study, we offer genetic evide nce that the apoptotic response of neoplastically transformed cells to DNA damage requires RhoB, a member of the Rho family of actin cytoskeletal regu lators. Targeted deletion of the rhoB gene did not affect cell cycle arrest in either normal or transformed cells after exposure to doxorubicin or gam ma irradiation, but rendered transformed cells resistant to apoptosis, This effect was specific insofar as rhoB deletion did not affect apoptotic susc eptibility to agents that do not damage DNA. However, rhoB deletion also af fected apoptotic susceptibility to Taxol, an agent that disrupts microtubul e dynamics. We have demonstrated that RhoB alteration mediates the proapopt otic and antineoplastic effects of farnesyltransferase inhibitors, and we s how here that RhoB alteration is also crucial for farnesyltransferase inhib itors to sensitize neoplastic cells to DNA damage-induced cell death. We fo und RhoB to be an important determinant of long-term survival in vitro and tumor response in vivo after gamma irradiation. Our findings identify a piv otal role for RhoB in the apoptotic response of neoplastic cells to DNA dam age at a novel regulatory point that may involve the actin cytoskeleton.