Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer
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Updated: Sep 23, 2025
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Beshara Sheehan1, Antje Neeb1, Lorenzo Buroni1
1The Institute of Cancer Research, London, UK.
Purpose:
Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression.
Experimental Design:
To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation.
Results:
The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion.
Conclusions:
The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA.
Insights
DNA damage can increase prostate-specific membrane antigen (PSMA) expression in cancer cells. This finding may improve outcomes for metastatic castration-resistant prostate cancer (mCRPC) patients receiving PSMA-targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Prostate-specific membrane antigen (PSMA) targeted therapies show promise for metastatic castration-resistant prostate cancer (mCRPC).
- Heterogeneous PSMA expression in mCRPC can lead to treatment resistance.
- Previous studies suggest a link between high PSMA expression and DNA damage repair defects.
Purpose of the Study:
- To investigate the hypothesis that DNA damage upregulates PSMA expression.
- To explore mechanisms underlying PSMA expression variability in mCRPC.
Main Methods:
- Screening of 147 FDA-approved anticancer agents and ionizing irradiation on tumor cells.
- In vitro validation in multiple prostate cancer cell lines (LNCaP, LNCaP95, 22Rv1).
- In vivo validation using a patient-derived xenograft model (CP286).
Main Results:
- Topoisomerase-2 inhibitors (daunorubicin, mitoxantrone) were identified to upregulate PSMA protein.
- Ionizing radiation also upregulated PSMA protein expression in a dose-dependent manner.
- Double-strand DNA breaks induced by these agents correlated with PSMA upregulation.
Conclusions:
- This study demonstrates for the first time that PSMA is upregulated in response to double-strand DNA damage from anticancer treatment.
- These findings support combining PSMA-targeted therapies with agents that induce DNA damage to enhance therapeutic efficacy.
- Upregulating PSMA expression could improve the effectiveness of PSMA-targeted treatment strategies in mCRPC.
