New vulnerability in prostate cancer identified
A multinational team of scientists has uncovered a promising vulnerability in prostate cancer cells that could improve how the disease is treated. In a study published in Proceedings of the National Academy of Sciences (PNAS), researchers from Flinders University in Australia and South China University of Technology demonstrate that two enzymes, PDIA1 and PDIA5, are critical for the growth, survival, and drug resistance of prostate cancer cells.
The findings position PDIA1 and PDIA5 as molecular bodyguards for the androgen receptor (AR), a key driver of prostate cancer. When these two enzymes are inhibited, the AR becomes unstable and breaks down, triggering cancer cell death and shrinking tumors in both laboratory models and animal studies. This discovery offers a new strategic angle to weaken cancer cells while potentially enhancing responses to existing therapies.
How PDIA1 and PDIA5 protect the androgen receptor
The research shows that PDIA1 and PDIA5 help stabilize the AR, enabling cancer cells to continue proliferating and resisting treatment. By blocking these enzymes, researchers observed a cascade of effects: the AR degraded more rapidly, prostate cancer cells lost their growth advantage, and treatment sensitivity improved. This dual mechanism—AR destabilization plus reduced cellular resilience—creates a more vulnerable cancer cell profile that is easier to kill with drugs.
Combining enzyme inhibitors with enzalutamide
One of the most striking aspects of the study is the synergy noted when PDIA1 and PDIA5 inhibitors are used alongside enzalutamide, a widely used AR-targeting therapy. In both patient-derived tumor samples and mouse models, the combination significantly boosted anti-tumor activity beyond what either approach achieved alone. This suggests a feasible path to overcoming treatment resistance that often develops with current hormone therapies.
The science behind a dual attack on cancer cells
Beyond AR stabilization, the PDIA1/PDIA5 duo appears to influence how cancer cells manage stress and generate energy. Blocking these enzymes disrupted mitochondrial function and heightened oxidative stress within cancer cells, compounding the anti-tumor effect. In essence, researchers are cutting off both the fuel (energy production) and the engine (mitochondrial resilience) of cancer cells, a combination that can push malignant cells past their breaking point.
Clinical implications and next steps
While the early data are encouraging, senior researchers caution that safe and effective inhibitors will require further development. Some current compounds may affect healthy cells, so the team emphasizes designing safer inhibitors and conducting rigorous clinical trials before these strategies reach patients. The aim is to translate the dual inhibition of PDIA1/PDIA5 into a viable therapy that can be combined with enzalutamide to extend patient survival and improve quality of life.
A promising advance for a common cancer
Prostate cancer remains the second most common cancer in men worldwide, and resistance to hormone therapies poses a major challenge. The discovery of PDIA1 and PDIA5 as dual targets offers a new route to augment current treatments, potentially redefining care for men with advanced disease. The international collaboration and support from numerous cancer charities and research funders underscore the broad interest in translating these findings into clinical benefit.
About the study
The study, titled “Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival,” was led by Professor Luke Selth of Flinders University and Professor Jianling Xie of South China University of Technology, with contributions from researchers across multiple institutions. The work was published in PNAS in 2025 and highlights a new mechanism by which the AR is regulated and a novel therapeutic angle for combination therapy.
