Sinomenine synergistically enhances 5-Fu anticancer effects in oral cancer through modulating the miR-140-5p-PDK1-anaerobic glycolysis pathway

Abstract

Oral squamous cell carcinoma (OSCC) is a type of human malignancy with a high mortality rate worldwide. Sinomenine (SIN), an active component of sinomenium acutum, has shown potential antitumor activities in various types of cancers. This study discovered that the combination of 5-Fu and SIN treatments had synergistic inhibitory effects on OSCC cells (CI < 1). Moreover, miRNA-140-5p was significantly downregulated in OSCC tumors and cell lines. Treatment with sinomenine upregulated miR-140-5p and suppressed anaerobic glycolysis of OSCC cells. We established a 5-Fu resistant OSCC cell line (CAL33 5-Fu R), which showed elevated anaerobic glycolysis and downregulated miR-140-5p. Through western blot, luciferase assay, and rescue experiments, we identified the pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme in anaerobic glycolysis, as a direct target of miR-140-5p, overexpression of which led to anaerobic glycolysis suppression and 5-Fu sensitization in OSCC cells. Furthermore, blocking the SIN-induced miR-140-5p successfully overcame the SIN-inhibited anaerobic glycolysis and 5-Fu resistance in OSCC cells. Meaningfully, results from in vivo mice xenograft experiments validated that sinomenine enhanced anti-cancer effects of 5-Fu treatment. Our findings reveal that the combination of sinomenine and 5-Fu synergistically enhances the cytotoxicity of OSCC cells by regulating the miR-140-5p-PDK1 axis.