New vulnerability uncovered in prostate cancer: targeting PDIA1 and PDIA5
A major international study has identified a promising vulnerability in prostate cancer cells that could improve how this common male cancer is treated. Published in the Proceedings of the National Academy of Sciences (PNAS), researchers from Flinders University in Australia and the South China University of Technology reveal that two enzymes, PDIA1 and PDIA5, help prostate cancer cells grow, survive, and resist current therapies.
At the heart of this discovery is the androgen receptor (AR), a protein that fuels the growth of many prostate tumors. The study shows that PDIA1 and PDIA5 act as molecular bodyguards for AR, stabilizing it and allowing cancer cells to thrive. When both enzymes are blocked, AR becomes unstable and breaks down, leading to cancer cell death and tumor shrinkage in laboratory models and mouse experiments.
Lead author Professor Jianling Xie, now at the South China University of Technology, explains that this mechanism was previously unknown. “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,” she says. Senior author Professor Luke Selth of Flinders University emphasizes the potential clinical impact: “By targeting these enzymes, we can destabilize the AR and make tumours more vulnerable to existing therapies like enzalutamide.”
Combining PDIA inhibition with enzalutamide enhances effectiveness
The research team tested the effect of combining PDIA1/PDIA5 blockers with enzalutamide, a widely used drug that targets AR signaling. In patient-derived tumor samples and animal models, the combination produced significantly stronger anti-tumor responses than either approach alone. These results suggest a practical path toward improving outcomes for men with advanced prostate cancer who eventually develop resistance to standard AR-targeted therapies.
Dr. Xie notes the encouraging findings come from multiple angles. “The synergy observed with enzalutamide supports the idea that dual enzyme inhibition can sensitize tumors to existing treatments, potentially delaying resistance and extending patient survival.”
Beyond AR protection: PDIA1/PDIA5 and cancer cell energy management
Interestingly, the enzymes do more than shield AR. The study reveals that PDIA1 and PDIA5 help cancer cells manage cellular stress and sustain energy production. When these enzymes are blocked, cancer cells suffer mitochondrial damage, experience oxidative stress, and lose the ability to generate energy effectively. The combined assault on AR stability and energy supply makes cancer cells more vulnerable and less capable of resisting therapy.
Professor Selth likens the effect to “cutting off both the fuel and the engine at the same time,” a powerful metaphor for how these enzymes sustain tumor growth. This dual action makes PDIA1 and PDIA5 attractive targets for future cancer therapies that could be used with or without enzalutamide.
From bench to bedside: what lies ahead
While the results are promising, translating them into safe, effective human treatments will require careful development. Current PDIA1/PDIA5 inhibitors show potential but must be refined to minimize effects on healthy cells. The researchers acknowledge that drug safety and tolerability will be central to any future clinical trials, with a focus on creating highly selective inhibitors that target cancer cells preferentially.
Prostate cancer remains the second most common cancer in men worldwide, and resistance to hormone therapy and AR-targeted drugs poses a major treatment challenge. The discovery of PDIA1 and PDIA5 as key players opens a new front in the fight against the disease, offering hope for improved therapies for patients with advanced prostate cancer.
Credits and funding
The study, titled “Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival,” involved researchers from Flinders University (Australia) and the South China University of Technology (China). It was supported by Cancer Councils, research foundations, and international funding bodies, including Australia’s ARC and Movember Foundation, underscoring the global effort to advance prostate cancer care.
In sum, blocking two enzymes—PDIA1 and PDIA5—emerges as a novel strategy to weaken prostate tumors and boost the effectiveness of existing drugs like enzalutamide, marking a potential turning point in the management of this pervasive disease.
