Epigallocatechin-3-gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer-associated fibroblasts
Epigallocatechin-3-gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer-associated fibroblasts
复制标题
DOI：
10.3892/ijo.2022.5309
复制
发表时间：
2022-02-01
影响因子：
5.2
通讯作者：
Wada, Yuma
中科院分区：
文献类型：
--
作者：
Chen, Shuhai;Nishi, Masaaki;Wada, Yuma
近年来，肿瘤代谢研究人员越来越关注肿瘤微环境。新出现的证据证实，癌症相关成纤维细胞（CAFs）的表观遗传修饰改变了葡萄糖代谢的特征，从而实现与癌细胞的共生关系。表没食子儿茶素-3-没食子酸酯（EGCG）通过多种机制发挥抗肿瘤作用，尽管EGCG影响cas葡萄糖代谢改变的潜在机制尚未阐明。在本研究中，通过与结直肠癌（CRC）细胞共培养，人肠成纤维细胞转化为CAFs，并表现出增强的有氧糖酵解。体外诱导的CAFs能够增强结直肠癌细胞的增殖、迁移和侵袭能力。EGCG直接抑制结直肠癌细胞的增殖和迁移；此外，EGCG处理CAFs通过抑制其糖酵解活性来抑制其促肿瘤能力。使用单羧酸转运蛋白4 （MCT4）抑制剂或通过沉默MCT4阻断CAFs的乳酸外排也可以抑制其促肿瘤能力，这表明乳酸在CAFs与癌细胞之间的代谢偶联中发挥重要作用。综上所述，本研究结果表明，EGCG靶向肿瘤基质细胞代谢提供了一种安全有效的抗癌治疗策略。
In recent times, researchers working on tumor metabolism have paid increasing attention to the tumor microenvironment. Emerging evidence has confirmed that epigenetic modifications of cancer-associated fibroblasts (CAFs) alters the characteristics of glucose metabolism to achieve a symbiotic relationship with the cancer cells. Epigallocatechin-3-gallate (EGCG) exerts anti-tumor effects via a variety of mechanisms, although the underlying mechanism that accounts for the effects of EGCG on glucose metabolic alterations of CAFs have yet to be elucidated. In the present study, through co-culture with colorectal cancer (CRC) cells, human intestinal fibroblasts were transformed into CAFs, and exhibited enhanced aerobic glycolysis. Induced CAFs were able to enhance the proliferation, migration and invasion of CRC cells in vitro. EGCG treatment led to direct inhibition of the proliferation and migration of CRC cells; furthermore, EGCG treatment of CAFs suppressed their tumor-promoting capabilities by inhibiting their glycolytic activity. Blocking the lactic acid efflux of CAFs with a monocarboxylate transporter 4 (MCT4) inhibitor or through silencing MCT4 could also suppress their tumor-promoting capabilities, indicating that lactate fulfills an important role in the metabolic coupling that occurs between CAFs and cancer cells. Taken together, the results of the present study showed that EGCG targeting of the metabolism of tumor stromal cells provided a safe and effective strategy of anti-cancer therapy.