title: PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer.
abstract: Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the β1integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/β1integrin axis may occur in other tumors.
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Leslie Ann
authors.identifier: http://orcid.org/0000-0003-2193-5190
authors.initials: LA
authors.lastname: Caromile
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dortche
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: M Mamunur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Grant
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0002-7137-761X
authors.initials: C
authors.lastname: Stoddard
authors.affiliation: Department of Urology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Ferrer
authors.affiliation: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA. lshapiro@uchc.edu.
authors.forename: Linda H
authors.identifier: http://orcid.org/0000-0003-4590-4671
authors.initials: LH
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D043425:Glutamate Carboxypeptidase II / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D043425:Glutamate Carboxypeptidase II; C579805:PSMA protein, mouse