title: Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance.
abstract: Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4-2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (>60-fold) and protein (>15-fold) levels, in castration-resistant (C4-2) cells as compared with androgen-dependent (LNCaP) prostate cancer cells of the same genotypic lineage. Using loss and gain of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and -deprived conditions, respectively, through induction of cyclins (A1, D1 and E1), Bcl-xL and Bcl2 and downregulation of p27 and Bax. Interestingly, Myb overexpression is also associated with enhanced prostate-specific antigen expression. Furthermore, our data show a role of Myb in enhanced motility and invasion and decreased homotypic interactions of prostate cancer cells. Myb overexpression is also associated with actin reorganization leading to the formation of filopodia-like cellular protrusions. Immunoblot analyses demonstrate gain of mesenchymal and loss of epithelial markers and vice versa, in Myb-overexpressing LNCaP and -silenced C4-2 cells, respectively, indicating a role of Myb in epithelial to mesenchymal transition. Altogether, our studies provide first experimental evidence for a functional role of Myb in growth and malignant behavior of prostate cancer cells and suggest a novel mechanism for castration resistance.
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604-1405, USA.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Arun
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Steven
authors.initials: S
authors.lastname: McClellan
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Eddie
authors.initials: E
authors.lastname: Reed
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
mesh_terms: D000728:Androgens / Q000172:deficiency / Q000378:metabolism*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056750:Cyclin A1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000378:metabolism; D020626:Oncogene Proteins v-myb / Q000096:biosynthesis* / Q000235:genetics; D009919:Orchiectomy; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D011554:Pseudopodia; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000728:Androgens; C494811:BCL2L1 protein, human; C503745:CCNA1 protein, human; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D056750:Cyclin A1; D019927:Cyclin E; D015513:Oncogene Proteins; D020626:Oncogene Proteins v-myb; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C413374:p27 antigen; D019938:Cyclin D1; D017430:Prostate-Specific Antigen