Pak 1 in prostate cancer 1 P 21 activated kinase-1 ( Pak 1 ) promotes prostate tumor growth and microinvasion via inhibition of TGFβ expression and enhanced MMP 9 secretion *

P21 activated kinases (Paks) are major effectors downstream of small Rho family of GTPases. Among the six isoforms, Pak1 is the most ubiquitous and the best characterized member. Previous studies have shown that inhibition of Pak6, which is predominantly present in the prostate compared to other tissues, inhibit prostate tumor growth in vivo. Even though Pak1 has been identified in normal prostatic epithelial cells and cancer cells, its specific role in the development of prostate cancer remains unclear. We report here that highly invasive prostate cancer cells express significantly higher levels of Pak1 protein compared to non-invasive prostate cancer cells. Furthermore, prostate tumor tissues and prostate cancer metastasized to lungs showed higher expression of Pak1 compared to normal tissues. Interestingly, Pak6 protein expression levels did not change with the invasive/metastatic potential of the cancer cells or tumors. While inhibition of Pak1, and not Pak6, resulted in impaired PC3 cell migration, the effects of Pak1 knockdown on transendothelial migration (microinvasion), tumor growth and tumor angiogenesis was higher compared to Pak6 knockdown. Finally, gene array data revealed reduced expression of MMP9 with the ablation of either Pak1 or Pak6 gene expression in PC3 cells, whereas protein levels of TGFβ was significantly elevated with specific modulation of Pak1 activity or ablation of Pak1 gene. Our observations suggest that although some level of functional redundancy exists between Pak1 and Pak6 in prostate cancer cells, targeting Pak1 is a potential option for the management of prostate tumor growth, microinvasion and metastasis.