An international team of researchers from Australia and China has identified a crucial cellular weakness in prostate cancer that could lead to a new generation of highly effective targeted treatments for the disease, particularly in cases that have become resistant to existing drugs.
Headline Points
– Key Vulnerability Identified: The research focuses on two enzymes, PDIA1 and PDIA5, that prostate cancer cells rely on to grow, survive, and resist common treatments.
- – Molecular Bodyguards: The enzymes act as “molecular bodyguards” for the Androgen Receptor (AR), the protein that primarily fuels the growth of most prostate cancers.
- – Therapeutic Dual Impact: Blocking PDIA1 and PDIA5 not only destabilises and breaks down the AR, but also simultaneously disrupts the cancer cells’ mitochondria (energy factories), effectively crippling the tumour.
- – Institutions Involved: The study was co-led by scientists from Flinders University in Australia and the South China University of Technology.
Targeting the Cancer’s Shield
The collaborative research, published in a leading scientific journal, unveils a previously unknown mechanism that prostate cancer cells use to survive in the face of therapy. The key is the pair of enzymes, PDIA1 and PDIA5 (Protein Disulfide Isomerases), which work to protect the Androgen Receptor (AR), a protein essential for the cancer’s growth.
When a patient is treated with hormone therapies—such as enzalutamide, a widely used drug—the cancer often learns to mutate or adapt its AR to resist the treatment, leading to aggressive, drug-resistant disease.
Senior author, Professor Luke Selth from Flinders University, explained that by targeting PDIA1 and PDIA5, researchers can destabilise the AR, causing it to break down. “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,” Professor Selth noted. “By targeting these enzymes, we can make tumours more vulnerable to existing therapies.”
A Double Blow to Tumour Cells
The enzymes’ vulnerability offers a promising dual-impact therapeutic strategy. Beyond protecting the AR, the enzymes also help the cancer cells manage the high levels of oxidative stress and maintain energy production required for rapid growth.
The research demonstrated that when PDIA1 and PDIA5 were blocked in lab-grown cells and animal models:
- – The Androgen Receptor was destabilised, cutting off the primary growth signal.
- – Mitochondrial function was impaired, leading to energy depletion and increased oxidative stress, which further pushed the cancer cells toward death.
This combined effect suggests that new drugs designed to specifically inhibit PDIA1 and PDIA5 could potentially supercharge the effectiveness of existing treatments like enzalutamide.
“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,” added Professor Jianling Xie from the South China University of Technology.
The next crucial step, the research team noted, is to develop new PDI inhibitor drugs that are highly specific to PDIA1 and PDIA5, a challenge both the Australian and Chinese research groups are now actively pursuing.
