A Novel Role of Prostate-Specific Membrane Antigen in Telomere Stability in Prostate Cancer Cells

Abstract

Prostate-specific membrane antigen (PSMA) expression increases with prostate cancer (PCa) grade and progression; however, the role of PSMA in PCa progression remains poorly understood. Telomere stability is essential for the survival and genome stability of cancer cells. We found massive telomere DNA damage in PSMA-negative PCa cells (PC-3 and DU145) compared to PSMA-positive PCa (LNCaP) cells. The ectopic expression of PSMA suppressed telomere DNA damage in PC3 cells. PSMA inhibitor, 2-PMPA, and PSMA knockdown induced telomere DNA damage in PSMA-positive LNCaP cells but not in PSMA-negative PC-3 cells, suggesting that PSMA plays a critical role in telomere stability in PCa cells. In addition, we observed that inhibition of PSMA or inhibition of glutamate receptor, which mediates PSMA-dependent activation of AKT, suppressed AKT phosphorylation and caused telomere DNA damage. Furthermore, 2-PMPA-induced telomere DNA damage in LNCaP cells was associated with telomere aberrations, such as telomere-telomere fusions, sister-chromatid telomere fusions, and telomere breakages. AKT is reported to promote cell growth by stabilizing telomere association with telomere-binding proteins TRF1 and TPP1. We observed that TRF1 and TPP1 transfection of LNCaP cells attenuated the inhibitory effect of 2-PMPA on cell growth and telomere DNA damage. Together, these observations indicate that PSMA role in maintaining telomere stability in PCa cells is mediated by AKT. Thus, these studies reveal an important role of PSMA in maintaining telomere stability that can promote cell survival and, thereby, PCa progression. Implications: the role of PSMA in telomere stability suggests a strong correlation between PSMA expression and prostate cancer progression.

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“…PSMA might play a role in the repair of DNA damage as it was shown to stimulate phosphatidylinositol-3-kinase (PI3K)/ Akt-mediated survival signaling 10 which, in turn, facilitates DSB repair 11 . PSMA was also reported to promote telomere stability in an Akt-dependent manner while inhibition of PSMA increased telomere DNA DSB formation 12 . Furthermore, membranous PSMA expression was higher in DNA repair-deficient cells 13 suggesting that PSMA might compensate for reduced repair capacity in that genetic background.…”