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 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.

PSMA redirects MAPK to PI3K-AKT signaling to promote prostate cancer progression

“…In our recent work published in Science Signaling, 9 we demonstrate that expression of PSMA in prostatic epithelial cells directly underlies prostate tumor progression in vivo by crossing FOLH1 global knockout mice 10 (hereafter called PSMA knockout) with the well-characterized TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) murine model to study PC tumor progression in the absence of PSMA expression. We observed that the primary tumors in wild-type animals were larger than tumors in the PSMA knockout animals and were highly vascularized, with higher rates of progression from hyperplasia to adenocarcinoma.…”

Sox7 negatively regulates prostate‐specific membrane antigen (PSMA) expression through PSMA‐enhancer

“…This finding was further supported by a mouse model study which indicated that moderate PSMA expression facilitates prostate carcinogenesis in vivo . Increased PSMA expression has been shown to induce aneuploidy and activate AKT signaling, and the over‐expression of PSMA may promote prostate carcinogenesis through several different mechanisms. Our data suggest that inactivation of Sox7 may provide multiple advantages for prostate carcinogenesis because it leads to the aberrant activation of WNT signaling and the over‐expression of PSMA.…”

“…While PSMA is moderately expressed in benign and hyperplastic prostate tissues, its expression level has been shown to be associated with increased tumor stage . An increased level of PSMA expression may directly contribute to prostate cancer development because PSMA induces aneuploidy and activates AKT signaling . Furthermore, a mouse model study indicated that moderate PSMA expression facilitates prostate carcinogenesis .…”

A novel PSMA/GCPII‐deficient mouse model shows enlarged seminal vesicles upon aging

“…Out of three PSMA/GCPII‐deficient colonies established to date, only one (IMPC) had the PGK‐Neo cassette removed using the Cre‐Lox system before the mice were characterized . The other two PSMA/GCPII‐deficient colonies, which are routinely used for diverse experiments, likely do not contain any LoxP sites, and PGK‐Neo cassette removal is thus not possible.…”