Dual Enzyme Blockade Weakens Prostate Cancer Tumors and Enhances Treatment Effectiveness

Researchers have identified two enzymes that serve as critical guardians of prostate cancer cell survival, opening new avenues for enhancing treatment outcomes in one of the most common cancers affecting men worldwide. The study, published in the Proceedings of the National Academy of Sciences, demonstrates that blocking these molecular chaperones can destabilize cancer cells and significantly boost the effectiveness of existing therapies.​

The international collaboration between Flinders University in Australia and South China University of Technology reveals that protein disulfide isomerases PDIA1 and PDIA5 play an essential role in protecting the androgen receptor, the primary driver of prostate cancer progression. These enzymes function as molecular bodyguards, stabilizing the androgen receptor and ensuring its proper folding even under cellular stress conditions.​

When PDIA1 and PDIA5 are inhibited through either genetic knockdown or pharmacological blockade, the androgen receptor becomes unstable and undergoes proteasomal degradation. This destabilization triggers cancer cell death and produces measurable tumor shrinkage in both laboratory-cultured cells and animal models. The mechanism represents a previously unrecognized vulnerability in prostate cancer that could be exploited therapeutically.​

The study demonstrates that PDIA1 and PDIA5 are upregulated in prostate cancer and induced by androgen receptor signaling, creating a feedback loop between these chaperones and the receptor pathway. Mechanistically, these enzymes regulate androgen receptor stability by catalyzing disulfide bond formation within the receptor protein.

Beyond their role in androgen receptor stabilization, the enzymes support cancer cell metabolism and stress adaptation. When PDIA1 and PDIA5 are blocked, cancer cells experience mitochondrial dysfunction, impaired energy production, and elevated oxidative stress. This dual impact attacks both the receptor signaling that drives cancer growth and the metabolic machinery that sustains cancer cell survival.​

The most striking finding involves combination therapy. When PDIA1 and PDIA5 inhibitors were combined with enzalutamide, a widely prescribed androgen receptor antagonist, the treatment synergistically enhanced cancer cell death. This combination produced results far superior to enzalutamide alone, with cancer cells showing extensive signs of mitochondrial collapse and oxidative damage.​

The dual mechanism of simultaneously disrupting both androgen receptor signaling and cellular energy supply makes these enzymes particularly attractive therapeutic targets, comparing it to cutting off both the fuel and the engine at the same time.​

The combination therapy demonstrated efficacy in patient-derived tumor samples and mouse models, both of which closely replicate human tumor biology. These preclinical results suggest strong potential for clinical translation, with the research team advocating for future clinical trials to evaluate this approach in patients.​

Protein disulfide isomerases belong to a family of at least 21 enzymes primarily located in the endoplasmic reticulum, where they facilitate proper protein folding by catalyzing disulfide bond formation, breakage, and rearrangement. Multiple members of this enzyme family are upregulated in various cancers, where elevated protein production creates dependency on endoplasmic reticulum chaperones to maintain cellular proteostasis.​

Cancer cells exhibit accelerated protein synthesis to meet their high metabolic demands, creating vulnerability to disruption of protein folding machinery. This dependency is particularly pronounced in prostate cancer cells, which rely heavily on androgen receptor signaling for survival and proliferation.​

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