Abstract
Metformin, the first-line drug for type II diabetes, has recently been considered an anticancer agent. However, the molecular target and underlying mechanism of metformin’s anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.
Highlights
Chemotherapy is one of the most frequently used approaches to treat cancers [1], whereas the resistance to and toxicity of chemotherapeutic agents cause many problems in the clinical optimisation of chemotherapy [2, 3]
Agent metformin could be beneficial for solving this problem with chemotherapy, especially for chemotherapy with agents targeting one-carbon metabolism
We demonstrated that metformin inhibited a novel target, DHFR, through both transcriptional and posttranslational mechanisms, increasing the sensitivity of hepatocarcinoma cells to MTX and suppressing their proliferation (Fig. 6)
Summary
Chemotherapy is one of the most frequently used approaches to treat cancers [1], whereas the resistance to and toxicity of chemotherapeutic agents cause many problems in the clinical optimisation of chemotherapy [2, 3]. Since methotrexate (MTX), a traditional chemotherapeutic agent, interrupts onecarbon metabolism by inhibiting the synthesis of tetrahydrofolate [19], we considered that it might be a promising drug for combination with metformin in cancer therapy. We progression of MTX-resistant cells, the combination treatment found that metformin transcriptionally inhibits DHFR via significantly reduced the population of S-phase cells Restoration of DHFR expression or supplemolecular target of metformin to overcome resistance to MTX and mentation with a nucleotide mixture significantly attenuated the suppress cancer cell proliferation. Suppressive effect on cell numbers and the S-phase population caused by the combination treatment (Fig. 1I–L and Supplementary Fig. 1L–P) Taken together, these results demonstrate that metformin
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