title: αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor.
abstract: Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Pten(pc-/-), carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, because it is not regulated by a different αv-containing integrin, αvβ3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of αvβ6-expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor-increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy. Cancer Res; 76(17); 5163-74. ©2016 AACR.
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Carmine
authors.initials: C
authors.lastname: Fedele
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.affiliation: Biogen Inc., Cambridge, Massachusetts.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.affiliation: Program in Molecular Medicine and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
authors.affiliation: Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: FitzGerald
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania. Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. lucia.languino@jefferson.edu.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D011944:Receptors, Androgen; C073878:integrin alphavbeta6; D048055:Mitogen-Activated Protein Kinase 8