College of Life Science, Shanxi University, Taiyuan 030006, China.
The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China.
Int J Mol Sci. 2022 Mar 24;23(7):3544. doi: 10.3390/ijms23073544.
Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3'-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.
氟尿嘧啶（5-Fu）化疗耐药是结肠癌治疗失败的主要原因。因此，迫切需要探索一种安全有效的结直肠癌多药耐药逆转剂，这对于提高临床疗效具有重要意义。膳食类黄酮山奈酚在结直肠癌的发生和 5-Fu 耐药中起关键作用。然而，山奈酚逆转人结直肠癌细胞 5-Fu 耐药的分子机制尚不清楚。我们发现山奈酚可以逆转 HCT8-R 细胞对 5-Fu 的耐药性，表明山奈酚单独或与 5-Fu 联合使用具有治疗结直肠癌的潜力。众所周知，有氧糖酵解与肿瘤生长和化疗耐药有关。事实上，山奈酚处理显著降低了耐药结直肠癌细胞中的葡萄糖摄取和乳酸生成。在机制上，山奈酚促进结肠癌细胞中 microRNA-326（miR-326）的表达，miR-326 可以通过直接靶向丙酮酸激酶 M2 同工型（PKM2）3'-UTR（非翻译区）抑制糖酵解过程，抑制 PKM2 的表达，或间接阻断 PKM mRNA 的可变剪接因子，从而逆转结直肠癌细胞对 5-Fu 的耐药性。总之，我们的数据表明，山奈酚可能通过调节 miR-326-hnRNPA1/A2/PTBP1-PKM2 轴在克服 5-Fu 治疗耐药中发挥重要作用。
