Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression

Prostate Cancer cells are generally resistant to Apoptosis by conventional therapy. During a search for molecules that may overcome prostate Cancer cell survival mechanisms, we identified the prostate Apoptosis response-4 (Par-4) gene. Par-4 induced Apoptosis of selective prostate Cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway. Neither Fas pathway activation alone nor inhibition of NF-kappaB activity with IkappaB-super repressor was sufficient to induce Apoptosis of prostate Cancer cells. Coregulation of these two pathways was essential and sufficient for Par-4 to induce Apoptosis. On the other hand, prostate Cancer cells LNCaP or normal prostatic epithelial cells that were resistant to Apoptosis by Par-4 did not show Fas or FasL trafficking. These findings identify a mechanism of Apoptosis by Par-4 and suggest that Par-4 may have therapeutic potential.