Sharifi Masuda, Armstrong Cameron M, Ning Shu, Leslie Amy R, Schaaf Zachary A, Maine James P, Lou Wei, Li Pui-Kai, Xu Hongyu, Liu Chengfei, Gao Allen C
Department of Urologic Surgery, University of California at Davis, Davis, CA 95616, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Cancers (Basel). 2025 Jun 12;17(12):1959. doi: 10.3390/cancers17121959.
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.
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.
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.
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：人类固醇硫酸酯酶（STS）的表达在去势抵抗性前列腺癌（CRPC）中上调，并且与对恩杂鲁胺（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之间存在联系，但STS赋予这种表型的机制仍未完全了解。在本研究中，我们试图通过探索其在改变线粒体活性中的作用来了解STS如何在晚期前列腺癌（PCa）细胞中诱导治疗耐药性。
为了检查增加的STS表达对线粒体呼吸和编程的影响，我们在过表达STS的细胞（C4-2B STS）和恩杂鲁胺耐药的CRPC细胞（C4-2B MDVR）中进行了RNA测序（RNA-seq）分析、海马XF线粒体应激试验和线粒体复合体I酶活性测定。我们在C4-2B STS和C4-2B MDVR细胞上使用了STS的特异性化学抑制剂SI-2，并评估了STS活性抑制对线粒体分子途径和线粒体呼吸的影响。最后，我们研究了硫酸脱氢表雄酮（DHEAS）补充对C4-2B STS类器官的影响。
我们从C4-2B STS细胞的转录组分析中提供证据表明，参与氧化磷酸化、电子传递链和线粒体组织的代谢途径特征丰富。此外，在STS抑制后，电子传递链和线粒体组织途径中的信号明显减弱。海马XF线粒体应激试验和线粒体复合体I酶活性测定的结果表明，STS过表达增加线粒体呼吸，而SI-2对STS的抑制显著降低C4-2B STS细胞中的氧消耗率（OCR）和复合体I酶活性。同样，在C4-2B MDVR细胞中观察到OCR增加和电子传递链复合体I酶活性增加，而在SI-2抑制后OCR降低。最后，我们表明STS过表达促进DHEAS处理后的类器官生长。
我们的研究表明STS是晚期前列腺癌代谢重编程和灵活性的关键驱动因素。通过STS破坏增强的线粒体呼吸是改善CRPC治疗的一种有前景的策略。
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