PDF(Pubmed)
Abstract：
BACKGROUND: It is well established that hypercholesterolemia increases the risk of atherosclerosis, especially because it reduces the availability of nitric oxide (NO). However, the relationship between hypercholesterolemia and NO in regulating colorectal cancer development and progression remains unknown.
METHODS: We conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response.
RESULTS: Here, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction.
CONCLUSIONS: Our findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.
METHODS: We conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response.
RESULTS: Here, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction.
CONCLUSIONS: Our findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.
摘要：
背景：高胆固醇血症会增加动脉粥样硬化的风险，特别是因为它降低了一氧化氮（NO）的可用性。然而,高胆固醇血症和NO在调节结直肠癌发生和进展中的关系尚不清楚.
方法：我们进行了生物信息学分析，qRT-PCR,ChIP-qPCR分析，荧光素酶报告测定，克隆存活测定，和多个小鼠模型来研究高胆固醇血症在调节NO信号传导中的功能和机制。此外,NOS抑制剂用于评估治疗策略在抗肿瘤反应中的潜力。
结果：这里，我们显示氧化低密度脂蛋白(oxLDL)胆固醇及其受体LOX-1在高胆固醇血症诱导的结直肠肿瘤发生中至关重要.机械上,oxLDL促进氧化应激依赖性的缺氧信号诱导转录上调结直肠癌（CRC）细胞中NO合酶（NOS）尤其是NOS1的表达。更重要的是,我们的结果表明,用NOS1的特异性抑制剂Nω-丙基-L-精氨酸选择性抑制NOS1是高胆固醇血症相关性CRC的合适治疗策略,其疗效和毒性均可降低.
结论：我们的研究结果证实，高胆固醇血症诱导氧化应激依赖性的缺氧信号诱导转录上调CRC细胞中NOS1的表达，临床适用的NOS1抑制剂Nω-丙基-L-精氨酸代表了高胆固醇血症相关性CRC的有效治疗策略。
方法：我们进行了生物信息学分析，qRT-PCR,ChIP-qPCR分析，荧光素酶报告测定，克隆存活测定，和多个小鼠模型来研究高胆固醇血症在调节NO信号传导中的功能和机制。此外,NOS抑制剂用于评估治疗策略在抗肿瘤反应中的潜力。
结果：这里，我们显示氧化低密度脂蛋白(oxLDL)胆固醇及其受体LOX-1在高胆固醇血症诱导的结直肠肿瘤发生中至关重要.机械上,oxLDL促进氧化应激依赖性的缺氧信号诱导转录上调结直肠癌（CRC）细胞中NO合酶（NOS）尤其是NOS1的表达。更重要的是,我们的结果表明,用NOS1的特异性抑制剂Nω-丙基-L-精氨酸选择性抑制NOS1是高胆固醇血症相关性CRC的合适治疗策略,其疗效和毒性均可降低.
结论：我们的研究结果证实，高胆固醇血症诱导氧化应激依赖性的缺氧信号诱导转录上调CRC细胞中NOS1的表达，临床适用的NOS1抑制剂Nω-丙基-L-精氨酸代表了高胆固醇血症相关性CRC的有效治疗策略。
