Oxymatrine inhibits colorectal cancer metastasis via attenuating pkm2-mediated aerobic glycolysis

Abstract

Background: Colorectal cancer (CRC), a type of highly occurred intestinal cancer at present, is prone to metastasis at the later stage of chemotherapy. Looking for the anti-metastatic agents from natural compounds attracted much concern. Here, it aims to demon-strate whether oxymatrine, an anti-cancer natural compound, has anti-metastatic activity and its potential significance in clinic. Materials and Methods: Wound healing assay and transwell assay were for evaluating the effect of oxymatrine on cell migration and invasion in vitro. Anti-metastatic action in vivo was determined by hepatic metastasis of colorectal cancer cells in mice. Results: Oxymatrine can significantly inhibit cancer cell migration and invasion in vitro. The production of ATP, pyruvate, and lactate was suppressed in CRC cells under the treatment of oxymatrine, as well as the glucose consumption. Meantime, extracellular acidification rates (ECR) were evidently attenuated although the oxygen consumption rates (OCR) were not affected. Both clued that oxymatrine inhibition of metastasis is possibly related to blocking aerobic glycolysis. Subsequent results indicated that pyruvate kinase M2 (PKM2) not hexokinase (HK) and phosphofructokinase (PFK) were involved in oxymatrine blocking glycolysis as the PKM2 kinase activity and expression were inhibited by oxyma-trine and the PKM2 activator, TEPP-46, can reverse in part the effect of oxymatrine induced in CRC cells. Furthermore, this process was also mediated by inhibition of glucose trans-porter 1 (GLUT1). Finally, the in vivo metastatic model in mice showed both 20 mg/kg and 40 mg/kg oxymatrine significantly inhibit liver metastasis of CRC cells in mice, and PKM2 and GLUT1 expression in liver of the oxymatrine-treated group is declined. Conclusion: Oxymatrine exerted anti-metastatic activity dependent on inhibition of PKM2-mediated aerobic glycolysis. It is not only an anti-cancer agent but also a potential anti-metastatic compound with clinical application significance.