Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA.
J Exp Clin Cancer Res. 2022 Aug 11;41(1):242. doi: 10.1186/s13046-022-02419-w.
Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment.
TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models.
High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca-dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models.
These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.
子宫浆液性癌（USC）是最常见的非子宫内膜样子宫癌亚型，也是最具侵袭性的。大多数患者会死于逐渐产生耐药性的疾病，而开发能够靶向 USC 的新疗法仍然是一个主要的未满足的临床需求。本研究旨在确定在晚期 USC 中发现的新型不良预后生物标志物肌浆网钙释放通道蛋白 1（RYR1）赋予其恶性表型的分子机制，并通过重新定位 FDA 批准的化合物在 USC 治疗中靶向 RYR1 来证明其疗效。
分析 TCGA USC 数据集，以确定与患者生存或疾病阶段相关且可被 FDA 批准的化合物靶向的顶级基因。选择顶级基因 RYR1，并通过在体外和体内沉默和过表达 USC 细胞中的 RYR1 来确定 RYR1 在 USC 进展中的功能作用。通过反相蛋白阵列（RPPA）、Western blot 和转录组谱分析确定与 RYR1 在 USC 进展中的功能作用相关的分子机制和信号网络。使用体外和体内模型确定重新定位的化合物丹曲林钠对 USC 进展的疗效。
肿瘤中 RYR1 的高表达水平与疾病的晚期阶段相关。RYR1 的抑制通过 Ca 依赖性激活 AKT/CREB/PGC-1α 和 AKT/HK1/2 信号通路抑制增殖、迁移并增强凋亡，从而调节线粒体生物能学特性，包括氧化磷酸化、ATP 产生、线粒体膜电位、ROS 产生和 TCA 代谢物以及 USC 细胞的糖酵解活性。重新定位的化合物丹曲林钠抑制了 USC 进展和小鼠模型中的存活。
这些发现深入了解了 RYR1 调节 USC 恶性表型的机制，并有助于将丹曲林钠开发为 USC 治疗的重新定位治疗剂，以提高患者的生存率。
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