![]() Now there is a growing body of evidence that implicates fatty acid oxidation (FAO, or β-oxidation) as a critical aspect of lipid metabolism that drives PCa progression and treatment resistance, irrespective of fatty acid source. Īltered lipid metabolism is a well-characterised hallmark of PCa and, accordingly, significant research efforts have been made to target de novo lipogenesis and lipid uptake pathways. Targeting cancer metabolism has gained increasing attention as an attractive strategy to overcome resistance to AR-targeted therapies. Despite the development of potent androgen receptor (AR) pathway inhibitors, including enzalutamide (ENZ), these agents are not curative and patients with castrate-resistant prostate cancer (CRPC) eventually succumb to this disease. One of the main hurdles for the treatment of PCa is overcoming resistance to current androgen-targeting agents, which form the mainstay of therapy for locally advanced and metastatic PCa. Prostate cancer (PCa) remains the most diagnosed malignancy and the leading cause of cancer-related deaths in men globally. Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation. ![]() DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. ResultsĭECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Methodsīioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response. Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis.
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