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

• Published in: International journal of molecular sciences 2022-03, Vol.23 (7), p.3544
• Main Authors: Wu, Haili, Du, Jin'e, Li, Chenglu, Li, Hanqing, Guo, Huiqin, Li, Zhuoyu
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Acid production; Acid resistance; Alternative splicing; Apoptosis; Cancer therapies; Carrier Proteins; Cell Line, Tumor; Chemoresistance; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Drug resistance; Drug Resistance, Neoplasm - genetics; Flavonoids; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Humans; Kaempferol; Kaempferols; Kinases; Lactic acid; Membrane Proteins; MicroRNAs - metabolism; miRNA; mRNA; Multidrug resistance; Polypyrimidine Tract-Binding Protein - metabolism; Proteins; Pyruvate kinase; Pyruvic acid; Splicing; Splicing factors; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.