ABSTRACT
Apoptosis is one mechanism by which cancer cells can be eliminated. Therefore, understanding the signaling pathways that transduce apoptotic signals in cancer cells is an indispensable component of cancer research. Rac, a member of the Rho family of proteins, has been implicated in the regulation of cell survival and apoptosis. However, the mechanisms underlying this process remain to be elucidated. To understand the role of Rac in oral squamous cancer, we inhibited its activity by a Rac-specific small molecule inhibitor, NSC23766, or transfection of dominant negative Rac (Rac-DN), and discovered that inhibition of Rac activity elicits apoptosis in highly malignant oral squamous carcinoma (OSC-19) cells. Upon suppression of Rac, we observed up-regulation of c-Jun N-terminal kinase (JNK), leading to caspase-dependent apoptosis. Furthermore, stimulation of protein phosphatase (PP5) rescued apoptosis caused by Rac inhibition by dephosphorylating JNK. Taken together, inhibition of Rac activity leads to the suppression of PP5 activity, which results in extensive activation of JNK and caspase-dependent apoptosis. In conclusion, Rac inhibition may represent a novel therapeutic approach for oral squamous carcinoma.