Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer death in Americans and Western Europeans. The effectiveness of RNA interference in inhibiting the tumor development has been well established in various cancer types. In this study, we made an attempt to downregulate MMP-9, uPAR and Cathepsin B (Cat-B) in PC3 and DU145 prostate cancer cell lines. To achieve this, we used siRNA vectors encoding either one (monocistronic) or a combination (bicistronic) of MMP-9, uPAR and Cat-B. Matrigel invasion, in vitro angiogenesis and wound healing migration assays confirmed that the downregulation of MMP-9, uPAR and Cat-B inhibited cell invasive, angiogenic and migratory properties of both the prostate cancer cells lines tested. Further, the bicistronic siRNA vectors were more effective than monocistronic siRNA vectors in their ability to inhibit invasion, angiogenesis and migration. In addition, the siRNA treatments induced apoptosis of the tumor cells as determined by TUNEL and DNA laddering assays. An attempt to elucidate the apoptotic pathway showed the involvement of FAS/FADD-mediated activation of Caspases 8 and 7 in cleaving PARP, but not Caspase 3. Furthermore, orthotopic prostate tumors treated with siRNA vectors showed significant inhibition in tumor growth and migration as compared to untreated tumors. In conclusion, we report that the downregulation of MMP-9, uPAR and Cat-B using siRNA inhibits invasiveness and migration of prostate cancer cells and leads to apoptosis via activation of FAS and Caspase 8 both in vitro and in vivo.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 403.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009