title: ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.
abstract: While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Muniyan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Siu-Ju
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Zhengzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Parmender P
authors.initials: PP
authors.lastname: Mehta
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery/Urology, University of Nebraska Medical Center, Omaha, NE, USA; College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC. Electronic address: mlin@unmc.edu.
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics; D000726:Androgen Antagonists / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004721:Endoplasmic Reticulum; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000135:Acid Phosphatase; D000726:Androgen Antagonists; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C428439:prostatic acid phosphatase; C549870:KLK3 protein, human
keywords: Androgen sensitivity; Androgen-independent; ErbB-2; cPAcP and ERK1/2