Par-4 drives trafficking and activation of Fas and FasL to induce prostatecancer 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 ce ll survival mechanisms, we identified the prostate apoptosis response-4 (Pa r-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 ac tivation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway . Neither Fas pathway activation alone nor inhibition of NF-kappaB activity with I kappaB-super repressor was sufficient to induce apoptosis of prosta te cancer cells. Coregulation of these two pathways was essential and suffi cient for Par-4 to induce apoptosis, On the other hand, prostate cancer cel ls LNCaP or normal prostatic epithelial cells that were resistant to apopto sis 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 therapeut ic potential.