MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France.
Cell Death Dis. 2021 Oct 21;12(11):978. doi: 10.1038/s41419-021-04270-x.
Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.
结直肠癌 (CRC) 可分为四个共识分子亚型 (CMS)，其中 CMS1 的预后最好，与 CMS4 形成鲜明对比，CMS4 的预后最差。CMS4 CRC 对治疗干预具有明显的耐药性，这已被临床前研究和回顾性临床观察所证实。在这里，我们报告了一个发现，即两种临床应用的药物，依维莫司 (EVE) 和普卡霉素 (PLI)，能够有效地靶向典型的 CMS4 细胞系 MDST8。与典型的 CMS1 细胞系 LoVo 相比，用 EVE 或 PLI 处理的 MDST8 细胞表现出更强的细胞生长抑制和细胞毒性作用，增加了细胞凋亡和自噬的迹象，以及更明显的 DNA 到 RNA 转录和 RNA 到蛋白质翻译的抑制。此外，EVE 和 PLI 的无毒剂量可诱导 MDST8 肿瘤在小鼠体内缩小，但对 LoVo 肿瘤的生长抑制作用较小。总的来说，这些结果表明，应该评估 EVE 和 PLI 对 CMS4 CRC 的临床活性。
