An international team of researchers has discovered a new vulnerability in prostate cancer cells that could lead to more effective therapies for one of the most common cancers affecting men. The study, published in the Proceedings of the National Academy of Sciences (PNAS), was led by scientists from Flinders University, Australia, and South China University of Technology.
Key Enzymes Found to Protect Cancer Cells
The researchers identified two enzymes—PDIA1 and PDIA5—that play a vital role in helping prostate cancer cells grow, survive, and resist treatment. These enzymes act as molecular bodyguards for the androgen receptor (AR), a protein that drives prostate cancer progression.
When scientists blocked PDIA1 and PDIA5, the androgen receptor became unstable and degraded, causing cancer cells to die and tumors to shrink in both lab-grown models and animal studies.
Combining New Inhibitors with Existing Drugs Enhances Treatment
As reported by medicalxpress, the team also tested a combination of PDIA1 and PDIA5 inhibitors with enzalutamide, a widely used prostate cancer medication. Remarkably, this combination significantly enhanced the drug’s effectiveness against cancer cells.
“We’ve discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor,” explained Professor Luke Selth, senior author of the study and Head of Prostate Cancer Research at Flinders University. “By targeting these enzymes, we can destabilize the AR and make tumors more vulnerable to existing therapies like enzalutamide.”
Promising Results from Tumor Samples and Animal Models
Lead author Professor Jianling Xie, who began this research at Flinders University and now works at the South China University of Technology, highlighted the encouraging results. “This combination therapy worked well in patient-derived tumor samples and in mice, suggesting strong potential for future clinical trials,” said Dr. Xie.
He added, “PDIA1 and PDIA5 are not just helpers of cancer growth—they’re promising targets for new treatments that could complement current drugs.”
Targeting the Cancer’s Energy Source
Beyond protecting the androgen receptor, PDIA1 and PDIA5 also help cancer cells handle stress and produce energy. Blocking these enzymes damages the cancer cells’ mitochondria—the energy-producing centers—causing oxidative stress that further weakens the cells.
“This dual effect—disrupting both the AR and the cancer’s energy supply—makes these enzymes especially appealing as drug targets,” noted Dr. Xie. “It’s like cutting off both the fuel and the engine at the same time.”
Future Research and Clinical Implications
According to Professor Selth, while current PDIA1 and PDIA5 inhibitors show potential, more work is needed to ensure they are safe for patients. “Some existing compounds may also affect healthy cells,” he said. “Our next goal is to develop more selective and safer inhibitors that can be tested in clinical trials.”
A Step Toward Overcoming Drug Resistance
Prostate cancer is the second most common cancer among men worldwide. Although hormone therapy and androgen receptor-targeting drugs like enzalutamide have benefited many patients, drug resistance remains a major challenge.
This new discovery could pave the way for therapies that overcome resistance and improve outcomes for men with advanced prostate cancer.