Research ArticleCancer

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaag3326
DOI: 10.1126/scisignal.aag3326

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PSMA is more than a diagnostic marker

Detection of prostate-specific membrane antigen (PSMA) diagnoses aggressive prostate cancer and predicts poor prognosis in patients. Using mouse models and tumor cell cultures, Caromile et al. found that the presence of PSMA on the surface of prostate tumor cells directs proliferative signaling through one pathway over another by disrupting the interaction of a receptor tyrosine kinase complex with an intracellular scaffolding protein. The findings suggest that patients with PSMA-positive tumors may benefit from PI3K-AKT pathway inhibitors and reveal a tumorigenic role for this traditionally diagnostic marker.

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 β1 integrin 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/β1 integrin axis may occur in other tumors.

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