Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.
Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.
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类固醇硫酸酯酶刺激内分泌雄激素合成，是晚期前列腺癌的治疗靶点。
DOI：
10.1158/1078-0432.ccr-20-1682
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发表时间：
2020-11-15
期刊：
影响因子：
--
通讯作者：
Gao AC
中科院分区：
文献类型：
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作者：
Armstrong CM;Liu C;Liu L;Yang JC;Lou W;Zhao R;Ning S;Lombard AP;Zhao J;D'Abronzo LS;Evans CP;Li PK;Gao AC
大多数接受Enzalutamide或阿比特龙治疗的前列腺癌患者会产生耐药性。临床证据表明，尽管进行了抗雄激素治疗，但硫酸脱氢表雄酮（DHEAS）和生物活性脱氢表雄酮（DHEA）的血清水平仍保持在高范围内。通过类固醇硫酸酯酶（STS）将DHEAS转化为DHEA可能有助于持续的内分泌雄激素合成。在这里，我们确定STS对治疗耐药性的贡献，并探索靶向STS克服前列腺癌耐药性的潜力。在患者和细胞系中检查STS表达。在体外，使用STS特异性siRNA或新型STS抑制剂（STSi）调节STS活性和表达。检测细胞生长、集落形成、雄激素产生和基因表达。对用STSi处理的VCaP细胞进行RNAseq分析。用STSi（含或不含enzalutamide）处理小鼠，以确定其体内效应。STS在去势抵抗性前列腺癌（CRPC）患者和抵抗细胞中过表达。STS过表达增加分泌内雄激素合成、细胞增殖，并赋予对恩杂鲁胺和阿比特龙的耐药性。使用siRNA抑制STS抑制前列腺癌细胞生长。使用STSi靶向STS活性抑制STS活性，抑制AR转录活性，并减少抗性C4-2B和VCaP前列腺癌细胞的生长。STSi在体外和体内显著抑制耐药VCaP肿瘤生长，降低血清PSA水平并增强Enzalutamide治疗。这些研究表明，STS驱动内分泌雄激素合成和前列腺癌增殖。靶向STS代表了治疗CRPC和改善第二代抗雄激素治疗的治疗策略。
Most prostate cancer patients receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active dehydroepiandrosterone (DHEA) remain in the high range despite anti-androgen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer. STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNAseq analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSi with or without enzalutamide to determine their effects in vivo. STS is overexpressed in castration resistant prostate cancer (CRPC) patients and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses AR transcriptional activity, and reduces the growth of resistant C4–2B and VCaP prostate cancer cells. STSi significantly suppress resistant VCaP tumor growth, decrease serum PSA levels and enhance enzalutamide treatment in vitro and in vivo. These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second generation anti-androgen therapy.