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Abstract
Prostate Cancer (PCa) is the second leading cause of cancer related deaths among men in the United States. Transforming growth factor (TGF) is a pleiotropic cytokine involved in a variety of cellular functions. However, the exact role of TGF in cancer is highly controversial. Recent findings indicate that advanced stage cancers shun the tumor suppressive actions of TGF and inexplicably utilize the cytokine as a tumor promoter. In the current study, we sought to identify the role of TGF1 in PCa progression and metastasis. We first showed that treatment of metastatic prostate cancer (PC3) cells with TGF1 lead to enhanced apoptosis via activation of p38-MAPK, JNK/SAPK, and caspase-9, -6, and -3 accompanied by a decrease in PC3 cell proliferation, viability, and colony formation due to the inhibition of the ERK pathway. A PC3 subcutaneous xenograft study in athymic nude mice overexpressing TGF1 led to inhibition of tumor growth via activation of P38-MAPK and intrinsic apoptosis pathway. Intriguingly, we noticed a dual effect of TGF1on P21 activated kinase1 (Pak1) in PC3 cells, an enzyme involved in the actin-based cytoskeletal remodeling. Whereas in the short term TGF1inhibited Pak1, in the long term it activated Pak1 resulting in epithelial-to-mesenchymal transition (EMT). Interestingly, knockdown of the Pak1 gene resulted in enhanced TGF1 expression associated with a PC3 xenograft growth in nude mice. Subsequent studies revealed that TGF1 treatment increases Rac1 and Pak1 activity in PC3 and DU145 cells inducing cell scattering and increased expression of EMT markers such as Snail1 and N-cadherin. Treatment with a selective allosteric Pak1 inhibitor (IPA3) or knockdown of the Pak1 gene inhibited TGF1-mediated effects on PC3 and DU145 cell migration, scattering, and invasion accompanied with the suppression in EMT marker expression. Our results demonstrated for the first time that TGF1 differentially modulates prostate cancer cell apoptosis and invasion via regulation of the P38-MAPK and Pak1 pathway. TGF1 induces cytoskeletal remodeling, epithelial-to-mesenchymal transition, invasion and metastasis via regulation of Rac1-Pak1 signaling axis. These results suggest that TGF1 and/or the Rac1-Pak1 signaling axis may be potential therapeutic targets for the treatment of advanced-stage prostate cancer.