South Australian Immunogenomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, Australia.
Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Br J Cancer. 2024 Mar;130(5):741-754. doi: 10.1038/s41416-023-02557-8. Epub 2024 Jan 12.
Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. 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.
Bioinformatic 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. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa.
DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). 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. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation.
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.
过氧化物酶体是中央代谢细胞器，在脂肪酸稳态中具有关键作用。由于前列腺癌（PCa）特别依赖脂肪酸代谢，我们探讨了过氧化物酶体β-氧化（perFAO）对 PCa 活力和治疗反应的贡献。
对临床转录组数据集进行生物信息学分析，以确定过氧化物酶体β-氧化的酶 2,4-二烯酰辅酶 A 还原酶 2（DECR2）作为感兴趣的靶基因。在体外、体内和离体培养的临床前列腺肿瘤中，通过噻氯匹定检查 DECR2 和过氧化物酶体抑制的影响。转录组和脂质组学分析用于确定 DECR2 抑制在 PCa 中的功能后果。
DECR2 在临床 PCa 中上调，尤其是在转移性去势抵抗性 PCa（CRPC）中。DECR2 的耗竭显着抑制了一系列 CRPC 和治疗耐药性 PCa 细胞系的增殖、迁移和 3D 生长，并抑制了体内 LNCaP 肿瘤的生长和增殖。DECR2 影响细胞周期进程和脂质代谢以支持肿瘤细胞增殖。此外，过氧化物酶体和标准的雄激素受体抑制的共同靶向增强了对 PCa 细胞增殖的抑制作用。
我们的研究结果支持将过氧化物酶体，特别是 DECR2 作为 CRPC 的有前途的治疗靶标，并作为克服致命治疗抵抗的新策略。
