Study Reveals Prostate Cancer's Hidden Weak Spot, Two Key Enzymes Identified - Video

Scientists have discovered a critical weakness in prostate cancer cells involving two enzymes, PDIA1 and PDIA5, that protect the androgen receptor (AR)—a protein driving prostate cancer growth. A recent study published in the Proceedings of the National Academy of Sciences found that blocking these enzymes destabilizes the AR, causing cancer cells to die and tumors to shrink both in lab cultures and animal models.

Prostate cancer is the second most common cancer in men worldwide, and resistance to hormone therapies remains a significant challenge. Targeting PDIA1 and PDIA5 offers a novel strategy to overcome such resistance and improve patient outcomes, paving the way for more effective, combination treatment options in advanced prostate cancer management.

Prostate cancer cells rely on PDIA1 and PDIA5 as molecular bodyguards to maintain AR stability and resist treatment. When these enzymes were inhibited, the AR could not function properly and began breaking down. This not only led to cancer cell death but also made tumors more responsive to existing therapies like enzalutamide, a commonly prescribed AR-targeting drug.

Researchers from Flinders University, Australia, and South China University of Technology performed extensive experiments including patient-derived tumor samples and mouse models. Their findings showed impressive tumor shrinkage and enhanced treatment efficacy when PDIA1 and PDIA5 inhibitors were combined with enzalutamide.

Beyond AR protection, these enzymes help cancer cells manage stress and maintain energy production by supporting mitochondria, the cell’s powerhouses. Blocking PDIA1 and PDIA5 damages mitochondria, increases oxidative stress, and deprives cancer cells of energy—essentially cutting off both the “fuel” and “engine” that sustain tumor growth.

Lead researchers, including Professor Luke Selth and Dr. Jianling Xie, highlighted this dual impact as a promising therapeutic avenue. Although current inhibitors show potential, they require refinement to ensure safety and selectivity, as some may affect healthy cells.

REFERENCE: Jianling Xie, Kaikai Shen, Wenken Liang, Zijian Kuang, Raj K. Shrestha, Adrienne R. Hanson, Scott L. Townley, Meiling He, Sishu Yu, Peiwen Zhou, Liangzhen Zhu, Zhiwen Gong, Xiang Ao, Sushma R. Rao, Qing Zhang, Kaijie Chen, Jinfen Wei, Shashikanth Marri, Marten F. Snel, Swati Irani, Liye Chen, Ling Wang, Daniel P. McDougal, John B. Bruning, Minglin Ou, Shaobo Wang, Christopher G. Proud, Hongli Du, Lisa M. Butler, Luke A. Selth. Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival. Proceedings of the National Academy of Sciences, 2025; 122 (42) DOI: 10.1073/pnas.2509222122