title: Silencing of PMEPA1 accelerates the growth of prostate cancer cells through AR, NEDD4 and PTEN.
abstract: Androgen Receptor (AR) is the male hormone receptor and a nuclear transcription factor which plays a central role in the growth of normal and malignant prostate gland. Our earlier studies defined a mechanistic model for male hormone dependent regulation of AR protein levels in prostate cancer (CaP) cells through a negative feed-back loop between AR and PMEPA1, an androgen induced NEDD4 E3 ubiquitin ligase binding protein. This report focuses on the impact of PMEPA1 silencing on CaP biology. PMEPA1 knockdown accelerated the growth of CaP tumor cells in athymic nude mice. In cell culture models knockdown of PMEPA1 resulted in resistance to AR inhibitors enzalutamide and bicalutamide. While, AR protein down regulation by NEDD4 was PMEPA1 dependent, we also noted a PMEPA1 independent downregulation of PTEN by NEDD4. In a subset of human CaP, decreased PMEPA1 mRNA expression significantly correlated with increased levels of AR transcription target PSA, as a surrogate for elevated AR. This study highlights that silencing of PMEPA1 accelerates the growth of CaP cells through AR, NEDD4 and PTEN. Thus, the therapeutic restoration of PMEPA1 represents a promising complementary strategy correcting for AR and PTEN defects in CaP. Statement of significance: Here we define that silencing of PMEPA1 facilitates the growth of CaP cells and modulates AR through NEDD4 and PTEN. The restoration of PMEPA1 represents a promising complementary therapeutic strategy correcting for AR and PTEN defects.
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mohamed
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Shashwat
authors.initials: S
authors.lastname: Sharad
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Umeda
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Song
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Young
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.|Urology Service, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: McLeod
authors.affiliation: Joint Pathology Center, Silver Spring, MD 20910, USA.
authors.forename: Isabell A
authors.initials: IA
authors.lastname: Sesterhenn
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Taduru
authors.initials: T
authors.lastname: Sreenath
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Dobi
authors.affiliation: Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Shiv
authors.initials: S
authors.lastname: Srivastava
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D000075702:Nedd4 Ubiquitin Protein Ligases; D009570:Nitriles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014105:Tosyl Compounds / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D001549:Benzamides; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D009570:Nitriles; C412868:PMEPA1 protein, human; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen
keywords: NEDD4; PMEPA1; androgen receptor; enzalutamide; prostate cancer