A major international study has uncovered a new vulnerability in prostate cancer cells that could help improve treatment for one of the most common cancers affecting men.
The research, published in the journal Proceedings of the National Academy of Sciences (PNAS), was led by scientists from Flinders University in Australia and South China University of Technology.
It reveals that two enzymes — PDIA1 and PDIA5 — play a crucial role in helping prostate cancer cells grow, survive, and resist treatment.
These enzymes act as molecular bodyguards for the androgen receptor (AR), a protein that fuels prostate cancer. When PDIA1 and PDIA5 are blocked, the AR becomes unstable and breaks down, leading to cancer cell death and tumour shrinkage in both lab-grown cells and animal models.
The team also found that combining drugs that block PDIA1 and PDIA5 with enzalutamide, a widely used prostate cancer medication, significantly boosted the treatment's effectiveness.
"We've discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor, which is a key driver of the disease," says senior author, Professor Luke Selth, Head of Prostate Cancer Research and Co-Director of Flinders Health and Medical Research Institute's Cancer Impact program.
"By targeting these enzymes, we can destabilise the AR and make tumours more vulnerable to existing therapies like enzalutamide."
Lead author, Professor Jianling Xie, who started the research whilst at Flinders University, says that this combination therapy worked well in patient-derived tumour samples and in mice, suggesting strong potential for future clinical trials.
"This is an exciting step forward," says Dr Xie, now at South China University of Technology.
"Our findings show that PDIA1 and PDIA5 are not just helpers of cancer growth but they're also promising targets for new treatments that could work alongside existing drugs."
Interestingly, the role of these enzymes goes beyond protecting the AR. The study found that PDIA1 and PDIA5 also help cancer cells manage stress and maintain energy production.
Blocking them causes damage to the cells' mitochondria — the parts of the cell that generate energy — and leads to oxidative stress, which further weakens the cancer.
"This dual impact of hitting both the AR and the cancer's energy supply makes these enzymes especially attractive targets," adds Dr Xie.
"It's like cutting off both the fuel and the engine at the same time."
Professor Selth adds that while current drugs that block PDIA1 and PDIA5 show promise, more work is needed to make them safe and effective for use in patients. Some of the existing compounds may affect healthy cells, so future studies will focus on developing safer inhibitors.
Prostate cancer is the second most common cancer in men worldwide. Although treatments like hormone therapy and AR-targeting drugs have helped many patients, resistance to these therapies is a major challenge. This new discovery could help overcome that hurdle and improve outcomes for men with advanced prostate cancer.
The study was supported by Cancer Council SA, Cancer Council NSW, the Flinders Foundation, the Movember Foundation, Prostate Cancer Foundation of Australia, The Hospital Research Foundation, Cancer Australia, Masonic Charities Trust, Australian Research Council, and several international funding bodies.
The study, 'Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival' by Jianling Xie, Kaikai Shen, Wenken Liang, Zijian Kuang, Raj K. Shrestha, Adrienne R. Hanson, Scott L. Townley, Meiling He, Sishu Yu, Peiwen Zhou, Liangzhen Zhu, Zhiwen Gong, Xiang Ao, Sushma R. Raof, Qing Zhang, Kaijie Chen, Jinfen Wei, Shashikanth Marri, Marten F. Snel, Swati Irani, Liye Chen, Ling Wang, Daniel P. McDougal, John B. Bruning, Minglin Ou, Shaobo Wang, Christopher G. Proud, Hongli Du, Lisa M. Butler, and Luke A. Selth, was published in PNAS 2025;122:e2509222122
