Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

中文翻译：

---

用临床激动剂 Riociguat 刺激可溶性鸟苷酸环化酶抑制去势抵抗性前列腺癌的发生和进展


去势抵抗性前列腺癌 （CRPC） 是无法治愈且致命的，使前列腺癌成为美国男性第二大癌症相关死因。CRPC 是由于对标准护理雄激素剥夺 （AD） 治疗的治疗耐药性，由于分子机制不完全了解，并且缺乏持久的治疗选择。在这里，我们确定了增强的可溶性鸟苷酸环化酶 （sGC） 信号传导是抑制 CRPC 启动和生长的机制。与去势敏感阶段相比，侵袭性、致命性 CRPC 患者的 sGC 催化产物环状 GMP （cGMP） 血清水平显著降低。在从去势敏感前列腺癌 （CSPC） 群体中分离的新兴去势抵抗细胞中，专性 sGC 异二聚体通过其 β 亚基的甲基化被抑制。遗传消除 CSPC 细胞中 sGC 复合物的形成促进了 AD 诱导的衰老的逃避和伴随的去势抵抗性肿瘤生长。在已建立的去势抵抗细胞中，sGC 复合物存在，但处于可逆氧化和非活性状态。使 CRPC 细胞接受 AD 再生功能复合物，并与 FDA 批准的 sGC 激动剂 riociguat 共同处理，诱发氧化还原应激诱导的细胞凋亡。Riociguat 减少了去势抵抗性肿瘤的生长并增加了凋亡标志物，cGMP 水平升高与肿瘤负荷降低显著相关。Riociguat 治疗重组了肿瘤脉管系统并消除了缺氧肿瘤生态位，减少了 CD44 + 肿瘤祖细胞并增加了去势抵抗性肿瘤的放射敏感性。因此，本研究表明，增强 sGC 活性可以通过肿瘤细胞内在和外在效应抑制 CRPC 的出现和进展。 Riociguat 可以重新用于克服 CRPC，以无创监测 cGMP 水平作为靶向疗效的标志物。