title: Tpl2 induces castration resistant prostate cancer progression and metastasis.
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.
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Cho
authors.forename: Se Jeong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Song
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Cho
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Park
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Lee
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Hyun Moo
authors.initials: HM
authors.lastname: Lee
authors.forename: Han Yong
authors.initials: HY
authors.lastname: Choi
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human
keywords: castration resistance; metastasis; prostate cancer; tumor progression locus 2