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TARGETING TRAF6‐PAK1 SIGNALING LIMITS PROSTATE TUMOR GROWTH AND TGF&[Beta]1‐INDUCED PROSTATE CANCER CELL EPITHELIAL TO MESENCHYMAL TRANSITION
Author(s) -
Somanath Payaningal R,
AlAzayzih Ahmad,
Gao Fei
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1107.8
Subject(s) - du145 , prostate cancer , cancer research , epithelial–mesenchymal transition , pak1 , rac1 , transforming growth factor , cancer , prostate , transforming growth factor beta , metastasis , medicine , signal transduction , biology , microbiology and biotechnology , lncap
Recent studies demonstrate the dual role of transforming growth factor beta (TGFβ) in prostate cancer. It is not clear how TGFβ1 that suppresses early prostate tumor growth induces epithelial‐to‐mesenchymal transition (EMT) in advanced stages. We studied if P21‐activated kinase1 (Pak1), a serine‐threonine kinase that mediates cytoskeletal remodeling is necessary for the TGFβ1 induced prostate cancer EMT. Effects of TGFβ1 on control prostate cancer PC3 and DU145 cells and those with Pak1 inhibitor IPA 3 and siRNA mediated Pak1 inhibition were tested for prostate tumor xenograft in vivo and EMT in vitro . TGFβ1 inhibited PC3 tumor xenograft growth via activation of P38‐MAPK and caspase‐3, 9. Long‐term stimulation with TGFβ1 induced PC3 and DU145 cell scattering and increased expression of EMT markers such as Snail and N‐cadherin through tumor necrosis factor receptor‐associated factor‐6 (TRAF6)‐mediated activation of Rac1/Pak1 pathway. Selective inhibition of Pak1 using IPA 3 or knockdown using siRNA both significantly inhibited TGFβ1‐induced prostate cancer cell EMT and expression of mesenchymal markers. Our study demonstrated that TGFβ1 induces apoptosis and EMT in prostate cancer cells via activation of P38‐MAPK and Rac1/Pak1 respectively. Our results reveal the potential therapeutic benefits of targeting TGFβ1‐TRAF6‐Pak1 pathway for advanced‐stage prostate cancer. Support or Funding Information Funds were provided by the UGA‐Research Foundation, Wilson Pharmacy Foundation, The American Legion, and the NIH (R01HL103952) grants to PRS. Al‐Azayzih was supported by pre‐doctoral fellowship from Jordan University of Science and Technology. This material is the result of work supported with resources and the use of facilities at the Charlie Norwood VAMC, Augusta, GA.