4.7 Article

Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis

Journal

Publisher

MDPI
DOI: 10.3390/ijms23073544

Keywords

kaempferol; 5-Fu resistance; miR-326; PKM2; aerobic glycolysis; colorectal cancer

Funding

  1. National Natural Science Foundation of China [82072718, 31800290, 31770382]
  2. Project of the Central Government Guiding Local Science and Technology [YDZX20201400001436]
  3. Science and Technology Innovation Project of Colleges and Universities in Shanxi Province [2019L0027]

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Resistance to 5-Fluorouracil (5-Fu) chemotherapy is a major obstacle in colon cancer treatment. This study found that the dietary flavonoid kaempferol can reverse the drug resistance of colorectal cancer cells to 5-Fu, suggesting a potential treatment option. The mechanism behind this reversal involves the regulation of the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis and inhibition of glycolysis.
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.

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