ArticleCancer research2025
Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.Research (Washington, D.C.) · 2026Review
- Network Pharmacology and Experimental Validation Identify Paeoniflorin as a Novel SRC-Targeted Therapy for Castration-Resistant Prostate Cancer.Pharmaceuticals (Basel, Switzerland) · 2025Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
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. In this study, 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 with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer 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 cotreatment 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 the 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. Significance: Soluble guanylyl cyclase signaling inhibits castration-resistant prostate cancer emergence and can be stimulated with FDA-approved riociguat to resensitize resistant tumors to androgen deprivation, providing a strategy to prevent and treat castration resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.