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Tpl2 induces castration resistant prostate cancer progression and metastasis
Author(s) -
Lee Hye Won,
Cho Hyun Jung,
Lee Se Jeong,
Song Hye Jin,
Cho Hee Jin,
Park Min Chul,
Seol Ho Jun,
Lee JungIl,
Kim Sunghoon,
Lee Hyun Moo,
Choi Han Yong,
Nam DoHyun,
Joo Kyeung Min
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29248
Subject(s) - prostate cancer , cancer research , protein kinase b , metastasis , cxcr4 , pi3k/akt/mtor pathway , tumor progression , epithelial–mesenchymal transition , medicine , kinase , signal transduction , cancer , biology , microbiology and biotechnology , receptor , chemokine
Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial–mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro , proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo , Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT‐related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.