Ling Zhang, Clara I Troccoli, Beatriz Mateo-Victoriano, Laura Misiara Lincheta, Erin Jackson, Ping Shu, Trisha Plastini, Wensi Tao, Deukwoo Kwon, X Steven Chen, Janaki Sharma, Merce Jorda, Surinder Kumar, David B Lombard, James L Gulley, Marijo Bilusic, Albert C Lockhart, Annie Beuve, Priyamvada Rai
{"title":"用临床激动剂Riociguat刺激可溶性鸟苷酸环化酶可抑制阉割耐药前列腺癌的发展和恶化","authors":"Ling Zhang, Clara I Troccoli, Beatriz Mateo-Victoriano, Laura Misiara Lincheta, Erin Jackson, Ping Shu, Trisha Plastini, Wensi Tao, Deukwoo Kwon, X Steven Chen, Janaki Sharma, Merce Jorda, Surinder Kumar, David B Lombard, James L Gulley, Marijo Bilusic, Albert C Lockhart, Annie Beuve, Priyamvada Rai","doi":"10.1158/0008-5472.CAN-24-0133","DOIUrl":null,"url":null,"abstract":"<p><p>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. 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引用次数: 0
摘要
阉割抵抗性前列腺癌(CRPC)是一种无法治愈的致命疾病,使前列腺癌成为美国男性第二大癌症死因。CRPC是对常规雄激素剥夺(AD)治疗产生耐药性的结果,其分子机制尚不完全清楚,缺乏持久的治疗方案。在这里,我们发现可溶性鸟苷酸环化酶(sGC)信号的增强是抑制CRPC启动和生长的一种机制。侵袭性、致命性CRPC患者血清中sGC催化产物环GMP(cGMP)的水平明显低于对阉割敏感的患者。在从对绝经敏感的前列腺癌(CSPC)群体中分离出的新出现的绝经抗性细胞中,必须的sGC异二聚体通过其β亚基的甲基化而受到抑制。在 CSPC 细胞中从基因上废除 sGC 复合物的形成,可促进逃避 AD 诱导的衰老,同时促进耐阉割肿瘤的生长。在已建立的抗阉割细胞中,sGC复合物虽然存在,但处于可逆氧化和非活性状态。将 CRPC 细胞置于 AD 中可再生出功能性复合物,与 FDA 批准的 sGC 激动剂 Riociguat 联合处理可诱发氧化还原压力诱导的细胞凋亡。Riociguat 降低了耐阉割肿瘤的生长,增加了凋亡标志物,cGMP 水平的升高与肿瘤负荷的降低有显著相关性。Riociguat 治疗重组了肿瘤血管,消除了缺氧肿瘤龛,减少了 CD44+ 肿瘤祖细胞,提高了阉割耐药肿瘤的放射敏感性。因此,本研究表明,增强sGC活性可通过肿瘤细胞内在和外在效应抑制CRPC的出现和进展。可将 Riociguat 重新用于治疗 CRPC,并将 cGMP 水平的无创监测作为靶向疗效的标志物。
Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.
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.
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.