Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, Yancheng No.1 People's Hospital, Yancheng, China.
Cell Death Dis. 2024 Sep 3;15(9):643. doi: 10.1038/s41419-024-07023-8.
This study investigates the potential anti-colorectal cancer (CRC) activity of IMT1, a novel specific inhibitor of mitochondrial RNA polymerase (POLRMT). Single-cell RNA sequencing data reveal that POLRMT is overexpressed in CRC cells. Additionally, elevated POLRMT expression was observed in local CRC tissues and cells, while its expression remained relatively low in colon epithelial tissues and cells. IMT1 significantly inhibited colony formation, cell viability, proliferation, cell cycle progression, and migration in both primary and immortalized CRC cells. Furthermore, IMT1 induced apoptosis and cell death in CRC cells. The inhibition of POLRMT by IMT1 disrupted mitochondrial functions in CRC cells, leading to mitochondrial depolarization, oxidative damage, and decreased ATP levels. Using targeted shRNA to silence POLRMT closely mirrored the effects of IMT1, showing robust anti-CRC cell activity. Crucially, the efficacy of IMT1 was diminished in CRC cells with silenced POLRMT. Contrarily, boosting POLRMT expression externally by a lentiviral construct promoted the proliferation and migration of CRC cells. Importantly, treatment with IMT1 or silencing POLRMT in primary colon cancer cells decreased the phosphorylation of Akt1-S6K1, whereas overexpression of POLRMT had the opposite effect. In nude mice, orally administering IMT1 potently restrained primary colon cancer xenograft growth. IMT1 suppressed POLRMT activity, disrupted mitochondrial function, hindered Akt-mTOR activation, and prompted apoptosis within the xenograft tissues. In addition, IMT1 administration suppressed lung metastasis of primary colon cancer cells in nude mice. These combined results highlight the robust anti-CRC activity of IMT1 by specifically targeting POLRMT.
本研究调查了 IMT1（一种新型的线粒体 RNA 聚合酶（POLRMT）特异性抑制剂）在抑制结直肠癌（CRC）中的潜在活性。单细胞 RNA 测序数据显示，POLRMT 在 CRC 细胞中过表达。此外，在局部 CRC 组织和细胞中观察到 POLRMT 表达升高，而在结肠上皮组织和细胞中其表达相对较低。IMT1 显著抑制原代和永生化 CRC 细胞的集落形成、细胞活力、增殖、细胞周期进程和迁移。此外，IMT1 诱导 CRC 细胞凋亡和死亡。IMT1 通过抑制 POLRMT 破坏 CRC 细胞中的线粒体功能，导致线粒体去极化、氧化损伤和 ATP 水平降低。使用靶向 shRNA 沉默 POLRMT 紧密模拟了 IMT1 的作用，表现出强大的抗 CRC 细胞活性。至关重要的是，沉默 POLRMT 后 CRC 细胞中 IMT1 的疗效降低。相反，通过慢病毒构建体外部增强 POLRMT 的表达促进了 CRC 细胞的增殖和迁移。重要的是，在原代结肠癌细胞中用 IMT1 处理或沉默 POLRMT 会降低 Akt1-S6K1 的磷酸化，而 POLRMT 的过表达则产生相反的效果。在裸鼠中，口服给予 IMT1 可强力抑制原代结肠癌细胞异种移植物的生长。IMT1 抑制 POLRMT 活性，破坏线粒体功能，阻碍 Akt-mTOR 激活，并在异种移植物组织中引发凋亡。此外，IMT1 给药抑制了裸鼠中原代结肠癌细胞的肺转移。这些综合结果突出了 IMT1 通过特异性靶向 POLRMT 发挥强大的抗 CRC 活性。
