A newly uncovered mechanism thought to be a weakness of prostate cancer cells could inspire a new and improved targeted treatment for the disease.
International research led by Flinders University in Australia and South China University of Technology revealed that two enzymes called PDIA1 and PDIA5 play a crucial role in helping prostate cancer cells grow, survive and resist treatment.
The enzymes act as “molecular bodyguards” for a prostate cancer-fueling protein called the androgen receptor (AR).
When PDIA1 and PDIA5 are blocked, the AR becomes unstable and breaks down, leading to cancer cell death and tumor shrinkage in both lab-grown cells and animal models, the researchers explained.
This newfound knowledge could also lead to a new way to enhance current drugs.
"Like most malignant cells, prostate cancer cells must speed up the production of proteins to enable rapid rates of proliferation. To deal with all of these new proteins, the cancer cells require specialised 'tools' to properly fold them and make sure they are functioning properly," study author professor Luke Selth, head of Prostate Cancer Research and co-director of Flinders Health and Medical Research Institute’s Cancer Impact program, told Newsweek.
"Our new study is an important advance in the field because we show that one of these 'tools'—enzymes call protein disulphide isomerase (PDI) A1 and A5—represent a previously unrecognised vulnerability of prostate cancer cells. More specifically, if we remove or block the function of these enzymes, then the cancer cells get very stressed and die."
Prostate cancer is the second-leading cause of cancer death in American men, causing about 1 in 44 men to die, according to American Cancer Society. This year, there will be an estimated 313,780 new cases of the disease and 35,770 deaths from it in total across the U.S.
While treatments like hormone therapy and AR-targeting drugs have helped many patients, this discovery could offer a solution for those resistant to current options and affected by more advanced forms of the disease.
The team also uncovered that combining drugs that block both enzymes with a widely used prostate cancer medication called enzalutamide 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,” said Selth in a statement. “By targeting these enzymes, we can destabilize the AR and make tumours more vulnerable to existing therapies like enzalutamide.”
Off to a strong start in the research process, the combination therapy worked well in patient-derived tumor samples and in mice, according to study author professor Jianling Xie of South China University of Technology.
“This is an exciting step forward,” said Xie. “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.”
The researchers also uncovered the enzymes play a role in helping cancer cells manage stress and maintain energy production. Blocking them causes disruption to the cells’ energy-generating mitochondria and leads to oxidative stress, which further weakens cancer.
“This dual impact of hitting both the AR and the cancer’s energy supply makes these enzymes especially attractive targets,” said Xie.
“It’s like cutting off both the fuel and the engine at the same time.”
While current drugs that block PDIA1 and PDIA5 show promise, more work is needed to make them safe and effective for use in patients and ensure existing compounds don’t affect healthy cells, according to Selth.
"First and foremost, we need to develop new PDI inhibitor drugs that are more specific to PDIA1 and PDIA5—our teams in Australia and China are working hard on this right now. We also think that such drugs would likely benefit from approaches that would target them to prostate cancer cells, because these enzymes have important functions across a range of cells and tissues in the body," Selth said.
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Update 10/15/25, 10:56 a.m. ET: This article was updated with additional information and comments from Luke Selth.
Reference
Xie, J., Shen, K., Liang, W., Kuang, Z., Shrestha, R. K., Hanson, A. R., Townley, S. L., He, M., Yu, S., Zhou, P., Zhu, L., Gong, Z., Ao, X., Raof, S. R., Zhang, Q., Chen, K., Wei, J., Marri, S., Snel, M. F., Irani, S., Chen, L., Wang, L., McDougal, D. P., Bruning, J. B., Ou, M., Wang, S., Proud, C. G., Du, H., Butler, L. M., & Selth, L. A. (2025). Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival. Proceedings of the National Academy of Sciences, 122. https://doi.org/10.1073/pnas.2509222122
