A groundbreaking international study has revealed a novel vulnerability in prostate cancer cells that could mark a significant leap forward in therapeutic approaches for one of the most prevalent malignancies affecting men worldwide. This landmark research, published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), was spearheaded by leading scientists from Flinders University in Australia in partnership with South China University of Technology. Their findings elucidate the critical involvement of two enzymes, PDIA1 and PDIA5, in the maintenance, survival, and treatment resistance of prostate cancer cells.
At the heart of this discovery lies the androgen receptor (AR), a well-established protein driver fueling the progression of prostate cancer. PDIA1 and PDIA5 serve as indispensable molecular chaperones, ensuring the stability and functional integrity of the AR within cancerous cells. Through complex biochemical interactions, these enzymes safeguard the AR from degradation, thereby enabling continuous oncogenic signaling that supports tumor growth. When the activities of PDIA1 and PDIA5 are inhibited, this protective effect disintegrates, triggering the destabilization and proteasomal breakdown of AR, ultimately inducing apoptosis in cancer cells and causing measurable tumor regression.
Critically, the researchers demonstrated that pharmacological inhibition of PDIA1 and PDIA5 not only undermines AR stability but also amplifies the therapeutic efficacy of enzalutamide—an androgen receptor signaling inhibitor widely used in prostate cancer treatment. This combination treatment synergistically impaired cancer cell viability far more effectively than enzalutamide alone, as confirmed in both laboratory cultured cells and multiple animal models. These results delineate a promising avenue to counteract the notorious resistance that often develops against conventional hormone therapies in advanced prostate cancer cases.
Professor Luke Selth, an eminent figure in prostate cancer research and senior author on the study, highlights the significance of the discovery: “We have uncovered a previously uncharacterized mechanism that prostate cancer cells exploit to shield the androgen receptor, a pivotal oncogenic driver. Targeting PDIA1 and PDIA5 disrupts this defense, rendering tumors more susceptible to existing anti-androgen therapies such as enzalutamide.” This insight opens a new frontier in the quest for therapeutic regimens that can overcome the adaptive resistance often encountered during treatment.
Contributing to the robustness of this research, lead author Professor Jianling Xie noted that the dual blockade of PDIA1 and PDIA5 exhibited potent anti-cancer effects in patient-derived tumor samples and in vivo mouse models, both of which closely mimic human tumor biology. “Our data strongly support the translational potential of this combination therapy, warranting further rigorous clinical trials that could eventually improve patient outcomes,” Dr. Xie explained, now continuing her research at South China University of Technology.
Beyond their role as molecular bodyguards of the androgen receptor, PDIA1 and PDIA5 were found to exert additional oncogenic functions by regulating cellular stress responses and bioenergetic homeostasis. The study highlighted that inhibiting these enzymes results in mitochondrial dysfunction, impairing energy production within cancer cells and elevating reactive oxygen species (ROS). This oxidative stress exacerbates cellular damage, synergizing with AR destabilization to compound tumor cell lethality.
This multifaceted attack—simultaneously impairing AR signaling and cellular metabolism—positions PDIA1 and PDIA5 as uniquely attractive therapeutic targets. According to Dr. Xie, “By cutting off both the fuel supply and the engine driving prostate cancer, we effectively starve and immobilize the tumor’s capacity to survive and expand.” This dual mechanism is particularly notable in the context of developing treatments that can circumvent therapeutic resistance and target cancer on multiple biological fronts.
However, Professor Selth cautioned that current inhibitors targeting PDIA enzymes are still in the developmental phase. While promising, some existing compounds lack specificity and may damage healthy cells, thereby posing safety concerns. Future research efforts will focus on the rational design of more selective and less toxic PDIA inhibitors, optimizing their pharmacological profiles to enhance clinical applicability and minimize off-target effects.
The relevance of these findings is underscored by the epidemiological burden of prostate cancer, which ranks as the second most common cancer among men globally. Despite advances in hormone therapy and AR-directed drugs, resistance remains a formidable barrier to long-term disease control, especially in advanced and metastatic stages. The identification of PDIA1 and PDIA5 as central players in this resistance mechanism heralds a potential paradigm shift in therapeutic strategies aimed at durable cancer suppression.
The study was funded by a consortium of organizations committed to cancer research, including Cancer Council SA, Cancer Council NSW, the Flinders Foundation, the Movember Foundation, the Prostate Cancer Foundation of Australia, The Hospital Research Foundation, Cancer Australia, the Masonic Charities Trust, the Australian Research Council, and several international collaborators. This collaboration underscores the global priority placed on tackling prostate cancer through innovative scientific inquiry.
Full elucidation of the mechanisms by which PDIA1 and PDIA5 stabilize the androgen receptor and support cancer metabolism provides a valuable framework for the development of next-generation combination therapies. Such approaches may not only extend survival but also improve the quality of life for men afflicted with this disease. The prospect of therapies that more comprehensively disrupt cancer cell survival pathways offers renewed hope in the ongoing battle against prostate cancer.
Moving forward, the translation of this preclinical research into clinical success will depend on meticulous drug development, coupled with carefully designed clinical trials to establish efficacy and safety in humans. The path from bench to bedside may be challenging, but the evidence presented heralds a promising future for men confronting this diagnosis.
Subject of Research: Animals
Article Title: Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival
News Publication Date: 17-Oct-2025
Web References: DOI: 10.1073/pnas.2509222122
References: Jianling Xie et al., PNAS, 2025;122:e2509222122
Image Credits: Professor Luke Selth, Flinders Health and Medical Research Institute (FHMRI) and College of Medicine and Public Health, Flinders University
Keywords: prostate cancer, androgen receptor, PDIA1, PDIA5, enzyme inhibition, enzalutamide, therapeutic resistance, mitochondrial dysfunction, oxidative stress, combination therapy, molecular chaperones, cancer metabolism
Tags: advancements in prostate cancer researchandrogen receptor in prostate cancercancer cell apoptosis mechanismsinternational cancer research collaborationmolecular chaperones in oncologynovel prostate cancer therapiesPDIA1 and PDIA5 enzymes in cancerprostate cancer treatment innovationsproteasomal degradation in cancer treatmenttargeting cancer cell vulnerabilitiestherapeutic approaches for prostate cancertumor growth regulation
