Background/Objective: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity. Methods: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids. Results: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment. Conclusions: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment.
背景/目的：人源类固醇硫酸酯酶（STS）在去势抵抗性前列腺癌（CRPC）中表达上调，并与恩杂鲁胺（Enza）和阿比特龙（Abi）等抗雄激素药物的耐药性相关。尽管已知STS过表达与治疗无反应性之间存在关联，但STS赋予此表型的具体机制尚未完全阐明。本研究旨在通过探索STS在改变线粒体活性中的作用，以理解其如何诱导晚期前列腺癌细胞产生治疗抵抗。方法：为探究STS表达增加对线粒体呼吸和编程的影响，我们在STS过表达细胞（C4-2B STS）和恩杂鲁胺耐药CRPC细胞（C4-2B MDVR）中进行了RNA测序分析、Seahorse XF线粒体压力测试以及线粒体复合物I酶活性测定。我们使用STS特异性化学抑制剂SI-2处理C4-2B STS和C4-2B MDVR细胞，并评估STS活性抑制对线粒体分子通路及线粒体呼吸的影响。最后，我们检测了硫酸脱氢表雄酮（DHEAS）补充对C4-2B STS类器官的影响。结果：C4-2B STS细胞的转录组分析显示，其代谢通路特征在氧化磷酸化、电子传递链和线粒体组织方面显著富集。此外，抑制STS后，电子传递链和线粒体组织通路中的信号传导明显减弱。Seahorse XF线粒体压力测试和线粒体复合物I酶活性测定结果表明，STS过表达可增强线粒体呼吸，而SI-2抑制STS则显著降低C4-2B STS细胞的耗氧率（OCR）和复合物I酶活性。同样，在C4-2B MDVR细胞中观察到OCR和电子传递链复合物I酶活性升高，而SI-2抑制后OCR降低。最后，我们发现STS过表达在DHEAS处理下促进类器官生长。结论：本研究证实STS是晚期前列腺癌代谢重编程和代谢可塑性的关键驱动因子。通过靶向STS破坏增强的线粒体呼吸，为改善CRPC治疗提供了具有前景的策略。
Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer
肿瘤(癌症)患者之家