通过FOXC1-介导的血清代谢重编程可以增强结直肠癌的生长和在血清限制下对5-FU的抵抗
Zhukai Chen1, Jiacheng Xu1, Kang Fang1
1Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Cell communication and signaling : CCS
|January 8, 2025
概括
结肠直肠癌细胞通过改变血清代谢来抵抗化疗. 剥夺血清素的细胞激活了一条促进癌症生长和5-fluorouracil耐药性的途径,建议新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 癌症新陈代谢 癌症新陈代谢
- 分子生物学分子生物学
背景情况:
- 大肠直肠癌 (CRC) 是一种主要的胃肠道恶性瘤,用5-Fluorouracil (5-FU) 治疗.
- 瘤代谢重编程,特别是血清代谢,对于5-FU耐药性至关重要.
- 在CRC中营养应激下血清代谢重编程的机制尚未完全理解.
研究的目的:
- 为了研究结肠直肠癌细胞如何适应在血清剥夺下血清代谢.
- 为了确定关键的分子通路和转录因子参与这种适应.
- 探索血清代谢,FOXC1和5-FU抵抗之间的联系.
主要方法:
- 在血清缺乏条件下的细胞培养.
- 对血清素合成途径 (SSP) 基因表达的分析.
- 西方涂抹和基因表达分析以研究信号通路 (ERK1/2-p-ELK1).
- FOXC1表达及其在调节代谢酶和5-FU耐药性的作用.
主要成果:
- 血清素缺失高调节SSP基因,增强CRC细胞生长和5-FU耐药性.
- ERK1/2-p-ELK1信号轴被血清缺乏激活,导致FOXC1表达的增加.
- FOXC1直接促进PHGDH,PSAT1和PSPH的转录,增加了血清蛋白的合成.
- 通过FOXC1介导的血清代谢会影响精氨酸代谢和DNA修复,从而导致5-FU耐药性.
结论:
- 结肠直肠癌细胞在血清合成中表现出代谢可塑性,以支持在血清缺乏下的生长和化学抵抗.
- 在CRC中,ERK1/2-p-ELK1-FOXC1轴是血清代谢和5-FU抗性的关键调节器.
- 针对这一轴结合饮食中血清限制可能为CRC提供一种新的治疗策略.
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