New vulnerability in prostate cancer identified: two enzymes that protect the androgen receptor
A major international study has uncovered a promising vulnerability in prostate cancer cells that could improve treatment for one of the most common cancers in men. Published in the Proceedings of the National Academy of Sciences (PNAS), the research shows that two enzymes, PDIA1 and PDIA5, help prostate cancer cells grow, survive, and resist therapy. By blocking these enzymes, the androgen receptor (AR) — a key driver of the disease — becomes unstable and breaks down, leading to cancer cell death and tumor shrinkage in lab experiments and animal models.
Researchers from Flinders University in Australia and South China University of Technology led the investigation, highlighting a mechanism by which prostate cancer cells shield the AR from degradation. This discovery points to a new therapeutic angle: targeting PDIA1 and PDIA5 to weaken the cancer’s core driver and improve responses to existing treatments.
How PDIA1 and PDIA5 protect the androgen receptor
The androgen receptor is central to the growth and survival of many prostate cancers. The study demonstrates that PDIA1 and PDIA5 act as molecular bodyguards, stabilizing the AR and helping cancer cells endure stress and persist despite therapy. When these enzymes are inhibited, AR stability declines, making cancer cells more vulnerable and less able to sustain tumor growth.
This dual control — undermining both AR stability and the cancer cells’ stress-management systems — suggests that PDIA1 and PDIA5 are not mere participants in cancer progression but active, targetable players. The finding offers a two-pronged approach: weaken the AR and disrupt the cancer cells’ energy and stress responses.
Combination therapy with enzalutamide shows promise
In addition to displaying AR destabilization, the research found that pairing inhibitors of PDIA1 and PDIA5 with enzalutamide, a widely used anti-androgen therapy, significantly boosted treatment efficacy. The combination was effective in patient-derived tumor samples and in mice, hinting at strong potential for clinical trials in humans.
Senior author Professor Luke Selth of Flinders University emphasized the significance: “We’ve discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor, a key driver of the disease. By targeting these enzymes, we can destabilize the AR and make tumours more vulnerable to existing therapies like enzalutamide.”
Implications for future research and treatment
Lead author Professor Jianling Xie noted that while the results are encouraging, more work is needed to translate them into safe, effective patient treatments. Some current PDIA1/PDIA5 inhibitors could affect healthy cells, so researchers are prioritizing the development of safer compounds and dosing strategies for clinical use. The study’s positive results in both lab tests and animal models support moving toward early-phase human trials.
Beyond AR protection, the enzymes also appear to influence cancer cell energy production and stress management. Blocking PDIA1 and PDIA5 can damage mitochondria and induce oxidative stress, further weakening tumor cells. This dual attack — undermining AR signaling and starving cancer cells of energy — makes these enzymes attractive targets for combination therapies aimed at overcoming resistance to current treatments.
Why this matters for men with prostate cancer
Prostate cancer remains the second most common cancer in men worldwide. While therapies that target AR signaling have extended many patients’ lives, resistance eventually develops in a large subset of cases. The discovery that PDIA1 and PDIA5 help protect AR, and that their inhibition can enhance responses to enzalutamide, offers a potential strategy to delay resistance and improve outcomes for men with advanced disease.
The study was supported by multiple organizations, including Cancer Council SA and the Movember Foundation, among others, reflecting broad international collaboration in the fight against prostate cancer. As researchers refine safer inhibitors, patients could benefit from a new, complementary approach that strengthens existing treatments.
About the study
The research, titled “Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival,” involved experts from Flinders University and South China University of Technology. It highlights PDIA1 and PDIA5 as pivotal in AR stability and prostate cancer cell viability, and it demonstrates the potential of combination therapy with enzalutamide. The work was published in PNAS in 2025 (PNAS 2025;122:e2509222122).
