Tpl2 induces castration resistant prostate cancer progression and metastasis

Hye Won Lee, Hyun Jung Cho, Se Jeong Lee, Hye Jin Song, Hee Jin Cho, Min Chul Park, Ho Jun Seol, Jung Il Lee, Sunghoon Kim, Hyun Moo Lee, Han Yong Choi, Do Hyun Nam, Kyeung Min Joo

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Abstract

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.

Original languageEnglish
Pages (from-to)2065-2077
Number of pages13
JournalInternational Journal of Cancer
Volume136
Issue number9
DOIs
Publication statusPublished - 2015 May 1

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, H. W., Cho, H. J., Lee, S. J., Song, H. J., Cho, H. J., Park, M. C., Seol, H. J., Lee, J. I., Kim, S., Lee, H. M., Choi, H. Y., Nam, D. H., & Joo, K. M. (2015). Tpl2 induces castration resistant prostate cancer progression and metastasis. International Journal of Cancer, 136(9), 2065-2077. https://doi.org/10.1002/ijc.29248