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[Cancer Research 61, 7255-7263, October 1, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

Par-4 Drives Trafficking and Activation of Fas and FasL to Induce Prostate Cancer Cell Apoptosis and Tumor Regression1

Mala Chakraborty, Shirley Guofang Qiu, Krishna Murthi Vasudevan and Vivek M. Rangnekar2

Departments of Radiation Medicine [M. C., S. G. Q., V. M. R.] and Microbiology and Immunology [K. M. V., V. M. R.], Graduate Center for Toxicology [V. M. R.], and L. P. Markey Cancer Center [V. M. R.], University of Kentucky, Lexington, Kentucky 40536

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-{kappa}B 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-{kappa}B activity with I{kappa}B-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.




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Copyright © 2001 by the American Association for Cancer Research.