An international team has discovered that prostate cancer cells depend on two enzymes, PDIA1 and PDIA5, for survival and resistance to therapy. Blocking these enzymes destabilizes the androgen receptor, leading to cancer cell death and improved drug efficacy. The findings, published in PNAS, suggest new ways to combat advanced prostate cancer.
Scientists from Flinders University in Australia and South China University of Technology have pinpointed a vulnerability in prostate cancer cells. Their study, published in the Proceedings of the National Academy of Sciences in 2025, reveals that the enzymes PDIA1 and PDIA5 act as protectors for the androgen receptor (AR), a protein essential for cancer growth.
When these enzymes are inhibited, the AR becomes unstable and degrades, causing cancer cells to die. This effect was observed in lab cultures and animal models, where tumors shrank. The researchers also found that combining PDIA1 and PDIA5 inhibitors with enzalutamide, a common prostate cancer drug, significantly boosted treatment 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 at Flinders Health and Medical Research Institute. "By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies like enzalutamide."
Beyond AR protection, PDIA1 and PDIA5 help cancer cells handle stress and sustain energy production. Inhibiting them damages mitochondria, the cell's energy generators, resulting in oxidative stress that further impairs the cells. "This dual impact of hitting both the AR and the cancer's energy supply makes these enzymes especially attractive targets," added lead author Professor Jianling Xie. "It's like cutting off both the fuel and the engine at the same time."
The study tested the approach in patient-derived tumor samples and mouse models, showing promise for clinical applications. However, current inhibitors may affect healthy cells, so future work will refine them for selectivity. Prostate cancer ranks as the second most common cancer in men worldwide, and resistance to hormone therapies remains a key challenge. This research, supported by organizations including Cancer Council SA and the Movember Foundation, could enhance options for advanced cases.