Targeting 'molecular bodyguards' weakens prostate cancer cells

A major international study, led by Flinders University and South China University of Technology, has uncovered a new vulnerability in prostate cancer cells that could help improve treatment for the second most common cancer in men worldwide.

As explained in the journal PNAS, the work reveals that two enzymes — PDIA1 and PDIA5 — act as ‘molecular bodyguards’ for the androgen receptor (AR), a protein that fuels prostate cancer. Although treatments like hormone therapy and AR-targeting drugs have helped many patients, resistance to these therapies is a major challenge.

Scientists have now found that 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,” said 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 while at Flinders University, said 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,” Xie said.

“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 study found that the role of these enzymes goes beyond protecting the AR — it turns out 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,” Xie said.

“It’s like cutting off both the fuel and the engine at the same time.”

Selth said 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 existing compounds may affect healthy cells, so future studies will focus on developing safer inhibitors.

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