Lee Yu Jin, Han Yeo Jeong, Oh Je Joung, Kim Seung-Young, Cho Jaehoon, Jung Ji Hoon
College of Korean Medicine, Kyung Hee University, Seoul, 02447, Korea.
Department of Life Science and Biochemical Engineering, Sunmoon University, Asan, 31460, Korea.
Genes Genomics. 2025 Jun 30. doi: 10.1007/s13258-025-01657-4.
OTOP3, a proton channel located at 17q25.1, drives colorectal cancer growth by enhancing c-Myc stability and inhibiting ferroptosis through GPX4 regulation. Inhibition of OTOP3 suppresses CRC proliferation via c-Myc destabilization, ROS accumulation, and lipid peroxidation, while modulating metabolic shifts linked to the Warburg effect. These findings position OTOP3 as a novel therapeutic target for CRC by disrupting oncogenic signaling and ferroptosis resistance.
To investigate OTOP3's role in CRC growth/metastasis and its link to ferroptosis and metabolic reprogramming. To evaluate OTOP3 targeting as a therapeutic strategy.
Colorectal cancer (CRC) cell lines were transfected with OTOP3 siRNA to suppress gene expression, followed by cell viability assays to assess proliferation changes. Western blotting quantified c-Myc and GPX4 levels, while fluorescent probes measured ROS accumulation and lipid peroxidation. Ferroptosis induction was validated using ferroptosis inhibitors, and glycolytic activity was analyzed via glycolysis-related gene expression and lactate production assays.
OTOP3 inhibition destabilized c-Myc, suppressed proliferation, and induced ferroptosis via GPX4 reduction, ROS accumulation, and lipid peroxidation. Altered glycolysis factors indicated enhanced Warburg effect.
Our study provides compelling evidence that targeting OTOP3 effectively suppresses colorectal cancer proliferation by reducing c-Myc protein stability and inducing ferroptosis. These effects are closely associated with metabolic shifts characteristic of the Warburg effect, emphasizing OTOP3 as a potential therapeutic target in colorectal cancer treatment.
OTOP3是一种位于17q25.1的质子通道，通过增强c-Myc稳定性和通过调节GPX4抑制铁死亡来驱动结直肠癌生长。抑制OTOP3可通过使c-Myc不稳定、ROS积累和脂质过氧化来抑制结直肠癌增殖，同时调节与瓦伯格效应相关的代谢转变。这些发现表明OTOP3是通过破坏致癌信号和铁死亡抗性来治疗结直肠癌的新靶点。
研究OTOP3在结直肠癌生长/转移中的作用及其与铁死亡和代谢重编程的关系。评估靶向OTOP3作为一种治疗策略。
用OTOP3 siRNA转染结直肠癌细胞系以抑制基因表达，随后进行细胞活力测定以评估增殖变化。蛋白质免疫印迹法定量c-Myc和GPX4水平，而荧光探针测量ROS积累和脂质过氧化。使用铁死亡抑制剂验证铁死亡诱导，并通过糖酵解相关基因表达和乳酸产生测定分析糖酵解活性。
抑制OTOP3使c-Myc不稳定，抑制增殖，并通过降低GPX4、积累ROS和脂质过氧化诱导铁死亡。糖酵解因子的改变表明瓦伯格效应增强。
我们的研究提供了令人信服的数据表明，靶向OTOP3通过降低c-Myc蛋白稳定性和诱导铁死亡有效地抑制结直肠癌增殖。这些效应与瓦伯格效应特有的代谢转变密切相关，强调OTOP3作为结直肠癌治疗中潜在的治疗靶点。
