title: Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.
abstract: Cofilin (CFL) is an F-actin-severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.
authors: Authors' Affiliations: Departments of Toxicology, Urology, Molecular and Cellular Biochemistry, and Pathology, University of Kentucky College of Medicine, Lexington, Kentucky; and Departments of Cancer Genetics and Urology, Roswell Park Cancer Institute, Buffalo, New York.
authors: Joanne
authors: J
authors: Collazo
authors: Beibei
authors: B
authors: Zhu
authors: Spencer
authors: S
authors: Larkin
authors: Sarah K
authors: SK
authors: Martin
authors: Hong
authors: H
authors: Pu
authors: Craig
authors: C
authors: Horbinski
authors: Shahriar
authors: S
authors: Koochekpour
authors: Natasha
authors: N
authors: Kyprianou
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051339:Actin Depolymerizing Factors; D016212:Transforming Growth Factor beta