Tpl2 induces castration resistant prostate cancer progression and metastasis |
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| Authors: | 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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| Affiliation: | 1. Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;2. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;3. Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;4. Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Center for Molecular Medicine, Samsung Biomedical Research Institute, Suwon, South Korea;5. Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea |
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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. |
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| Keywords: | prostate cancer castration resistance tumor progression locus 2 metastasis |
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