<p>Oxymatrine Inhibits Colorectal Cancer Metastasis via Attenuating PKM2-Mediated Aerobic Glycolysis</p>

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 demonstrate 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 oxymatrine 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 transporter 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.

Oxymatrine Attenuates Osteoclastogenesis via Modulation of ROS-Mediated SREBP2 Signaling and Counteracts Ovariectomy-Induced Osteoporosis

“…Oxymatrine (OMT) is a quinazine alkaloid extracted from Sophora flavescens which has been reported to exhibit various therapeutic effects, such as immunomodulation, anti-inflammation, anti-oxidation, anti-tumor, anti-virus, and hepatoprotection ( Lean et al, 2003 ; Lee et al, 2005 ; Jung et al, 2008 ; Huang et al, 2020 ; Li et al, 2020a , b ; Wang et al, 2020 ; Xiang et al, 2020 ). However, there is no report on the treatment of osteoporosis with OMT.…”

Genetic Mutations and Non-Coding RNA-Based Epigenetic Alterations Mediating the Warburg Effect in Colorectal Carcinogenesis

“…PKM2 has also been reported as a target for vitamin C treatment, by which it inhibits its phosphorylation at serine 37 residue of PKM2 [ 79 ]. Oxymatrine was found to inhibit metastasis and attenuate the aerobic glycolysis in CRC cells, and the inhibition was associated with the blocking of PKM2 activity [ 3 ]. These studies provide a novel insight into PKM2′s potential role in inducing CRC metastasis by enhancing the Warburg effect.…”

“…Inhibition of GLUT1 expression has been shown to be facilitated by a group of anti-cancer therapies, including DT-13, Oridonin, and Oxymatrine [ 2 , 3 , 97 ], and by butyrate, which functions as a glycolysis inhibitor in CRC cells [ 98 ]. However, it is still unclear whether butyrate affects GLUT1 expression as an HDAC inhibitor, thus warranting further studies.…”

“…Despite improvements in diagnosis and treatment, CRC causes approximately one million deaths per year and accounts for the thirdhighest cancer-related deaths worldwide [1]. Recently, anti-cancer drugs targeting dysregulated cancer cell metabolism have been gaining greater attention in the scientific commu-Biology 2021, 10, 847 2 of 16 nity [2,3]; therefore, understanding the metabolic pathways in CRC cells may provide a key for developing novel diagnostic and therapeutic options to overcome this disease.…”

Chinese Poplar Propolis Inhibits MDA-MB-231 Cell Proliferation in an Inflammatory Microenvironment by Targeting Enzymes of the Glycolytic Pathway

“…Cancer cells rely on higher rates of aerobic glycolysis as their primary source of energy; thus, aerobic glycolysis becomes a hallmark of cancer cells. Key enzymes of glycolysis, namely, hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase muscle isozyme M2 (PKM2), and lactate dehydrogenase A (LDHA), are critical glycolysis regulators [ 14 ]. Enhanced glycolysis correlates with the upregulation and activation of critical glycolytic enzymes, which, in turn, promotes proliferation, metastasis, and tumorigenesis [ 15 ].…”