State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Cancer Lett. 2023 Oct 1;573:216364. doi: 10.1016/j.canlet.2023.216364. Epub 2023 Aug 28.
Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.
异柠檬酸脱氢酶（IDH）1 和 2 作为能量代谢中的必需酶，有助于多种实体瘤的存活和耐药性，特别是结直肠癌（CRC）。然而，其潜在的分子机制仍不清楚。在这项研究中，我们使用无偏热蛋白质组谱（TPP）策略，发现 IDH1 是天然衍生抗 CRC 小分子石蒜碱的关键细胞靶标。我们发现石蒜碱直接靶向 IDH1 的独特 C 端结构域，并破坏 IDH1 与去乙酰化酶 SIRT1 的相互作用，从而显著促进 IDH1 乙酰化修饰。然后，石蒜碱明显在 CRC 细胞中引发氧化应激，导致线粒体膜损伤，随后促进线粒体分裂。IDH1 或 SIRT1 的特异性敲低显著加重了石蒜碱介导的 CRC 细胞中的氧化应激和线粒体碎片化。此外，石蒜碱和 SIRTINs 抑制剂烟酰胺（NAM）的联合使用在 CRC 细胞中表现出协同的治疗效果。总之，我们的研究结果表明，IDH1 可能通过药理学驱动氧化应激依赖性线粒体动力学失衡成为 CRC 的一个有前途的治疗靶点。
