title: P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor β expression and enhanced matrix metalloproteinase 9 secretion.
abstract: P21-activated kinases (Paks) are major effectors downstream of the 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 with other tissues, inhibits 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 with non-invasive prostate cancer cells. Furthermore, prostate tumor tissues and prostate cancer metastasized to lungs showed a higher expression of Pak1 compared with normal tissues. Interestingly, Pak6 protein expression levels did not change with the invasive/metastatic potential of the cancer cells or tumors. Although 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 with Pak6 knockdown. Finally, gene array data revealed reduced expression of matrix metalloproteinase 9 with the ablation of either Pak1 or Pak6 gene expression in PC3 cells, whereas protein levels of TGFβ was elevated significantly with specific modulation of Pak1 activity or ablation of the 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.
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia.
authors.forename: Anna
authors.initials: A
authors.lastname: Goc
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Azayzih
authors.forename: Maha
authors.initials: M
authors.lastname: Abdalla
authors.forename: Belal
authors.initials: B
authors.lastname: Al-Husein
authors.forename: Sravankumar
authors.initials: S
authors.lastname: Kavuri
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lee
authors.forename: Kelvin
authors.initials: K
authors.lastname: Moses
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000728:Androgens; D016212:Transforming Growth Factor beta; C429007:PAK6 protein, human; D054462:p21-Activated Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9