Hidden weakness makes prostate cancer self-destruct

The study, published in the Proceedings of the National Academy of Sciences (PNAS), was led by scientists from Flinders University in Australia and South China University of Technology. Their findings highlight two enzymes, PDIA1 and PDIA5, that play a key role in helping prostate cancer cells grow, survive, and resist existing treatments.

Enzymes That Protect Cancer Cells

According to the researchers, PDIA1 and PDIA5 act like molecular bodyguards for the androgen receptor (AR), a protein that drives prostate cancer growth. When these enzymes are blocked, the AR loses stability and breaks apart, causing cancer cells to die and tumors to shrink in both lab cultures and animal models.

The team also discovered that combining drugs that inhibit PDIA1 and PDIA5 with enzalutamide, a standard medication for prostate cancer, made the treatment significantly more effective.

“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,” explains senior author Professor Luke Selth, Head of Prostate Cancer Research and Co-Director of the Flinders Health and Medical Research Institute’s Cancer Impact program.

“By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies like enzalutamide.”

A Promising Combination Therapy

Lead author Professor Jianling Xie, who began the research at Flinders University, said the combination therapy worked well in both patient-derived tumor samples and mouse models, showing strong potential for clinical use.

“This is an exciting step forward,” says Dr. Xie, now based 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.”

Disrupting Cancer’s Energy Supply

The study also revealed that PDIA1 and PDIA5 do more than just protect the AR. They help cancer cells manage stress and maintain their energy production systems. When the enzymes are blocked, the mitochondria — the cell’s power generators — become damaged, leading to oxidative stress that further weakens the cancer cells.

“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.”

Next Steps Toward Safer Treatments

Professor Selth notes that while current PDIA1 and PDIA5 inhibitors are promising, they still need to be refined for patient use. Some existing compounds can affect healthy cells, so future studies will focus on designing safer and more selective versions.

Prostate cancer is the second most common cancer in men worldwide. Although treatments such as hormone therapy and AR-targeting drugs have greatly improved survival rates, resistance to these therapies remains a major challenge. This new discovery may help overcome that resistance and improve treatment options for men with advanced prostate cancer.

The research received support from Cancer Council SA, Cancer Council NSW, the Flinders Foundation, the Movember Foundation, the Prostate Cancer Foundation of Australia, The Hospital Research Foundation, Cancer Australia, Masonic Charities Trust, the Australian Research Council, and several international funding organizations.