title: The significance of dynamin 2 expression for prostate cancer progression, prognostication, and therapeutic targeting.
abstract: Dynamin 2 (Dyn2) is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. In this study, we investigated the implication of Dyn2 as a prognostic marker and therapeutic target for progressive prostate cancer (PCA). We evaluated Dyn2 protein expression by immunohistochemistry in two cohorts: men with localized PCA treated by retropubic radical prostatectomy (n = 226), and men with advanced/castrate-resistant PCA (CRPC) treated by transurethral resection of prostate (TURP) (n = 253). The role of Dyn2 in cell invasiveness was assessed by in vitro and in vivo experiments using androgen-responsive and refractory PCA preclinical models. Dyn2 expression was significantly increased across advanced stages of PCA compared to benign prostate tissue (P < 0.0001). In the CRPC cohort, high Dyn2 was associated with higher Gleason score (P = 0.004) and marginally with cancer-specific mortality (P = 0.052). In preclinical models, Dyn2 gene silencing significantly reduced cell migration and invasion in vitro, as well as tumor size and lymph node metastases in vivo. In isolated PCA cells, Dyn2 was found to regulate focal adhesion turnover, which is critical for cell migration; this mechanism requires full Dyn2 compared to mutants deficient in GTPase activity. In conclusion, Dyn2 overexpression is associated with neoplastic prostate epithelium and is associated with poor prognosis. Inhibition of Dyn2 prevents cell invasiveness in androgen-responsive and -refractory PCA models, supporting the potential benefit of Dyn2 to serve as a therapeutic target for advanced PCA.
authors.affiliation: Segal Cancer Center and Lady Davis Institute for Medical Research, Department of Oncology and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Liang Hong
authors.initials: LH
authors.lastname: Teng
authors.forename: Sabrina Daniela da
authors.initials: SD
authors.lastname: Silva
authors.forename: Krikor
authors.initials: K
authors.lastname: Bijian
authors.forename: Samir
authors.initials: S
authors.lastname: Al Bashir
authors.forename: Su
authors.initials: S
authors.lastname: Jie
authors.forename: Michael
authors.initials: M
authors.lastname: Dolph
authors.forename: Moulay A
authors.initials: MA
authors.lastname: Alaoui-Jamali
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D018572:Disease-Free Survival; D034285:Dynamin II / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D034285:Dynamin II
keywords: Cancer-specific mortality; castration resistance; dynamin; prostate cancer; therapeutic target