Matrine Promotes Human Myeloid Leukemia Cells Apoptosis Through Warburg Effect Mediated by Hexokinase 2

Abstract

Matrine, an alkaloid compound isolated from the medicinal plant Sophora flavescens, inhibits many types of cancer proliferation. However, the precise mechanism of the matrine antihuman chronic myeloid leukemia remains unclear. In this study, we showed that matrine significantly inhibited the cell proliferation and induced apoptosis by regulating Warburg effect through controlling hexokinases 2 (HK2) expression in myeloid leukemia cells. Interestingly, matrine inhibited the expression of HK2 mediated by reduction in c-Myc binding to HK2 gene intron and led to downregulation of HK2, which upregulated proapoptotic protein Bad and then induced apoptosis. We further demonstrated that matrine could synergize with lonidamine, an inhibitor of HK2, for the treatment of myeloid leukemia, both in vitro and in vivo. Taken together, our findings reveal that matrine could promote human myeloid leukemia cells apoptosis via regulating Warburg effect by controlling HK2.

RETRACTED: Matrine Protects Cardiomyocytes Against Hyperglycemic Stress by Promoting Mitofusin 2-Induced Mitochondrial Fusion

“…Matrine is an alkaloid found in plants from the genus Sophora ( Li et al, 2019b ), and has a variety of pharmacological effects, including anti-oxidative, anti-cancer, and anti-apoptotic effects ( Lin et al, 2019 ; Atef et al, 2020 ). Matrine was found to inhibit doxorubicin-induced cardiotoxicity by activating the adenosine monophosphate-activated protein kinase/uncoupling protein 1 signaling pathway ( Hu et al, 2019a ).…”

HK2 is associated with the Warburg effect and proliferation in liver cancer: Targets for effective therapy with glycyrrhizin

“…The Warburg effect confers a growth advantage on cancer cells and HK2 has a vital role in this process ( 9 , 19 ). High expression levels of HK2 have been observed in LC cells ( 20 , 21 ).…”

“…Phosphofructokinase-1, pyruvate kinase M2, pyruvate dehydrogenase kinase-1, lactate dehydrogenase and hexokinase-2 (HK2) have emerged as indispensable glycolytic enzymes that catalyze the Warburg effect ( 8 ). Among these glycolytic enzymes, HKs catalyze the irreversible first step of the glycolytic pathway in which glucose is phosphorylated to glucose-6-phosphate with the concomitant dephosphorylation of adenosine triphosphate ( 9 ). Notably, HK2 has been identified as a central player in the Warburg effect and has been proposed as a metabolic target for the development of cancer therapies ( 10 ).…”

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

“…Lin et al demonstrated that MAT induced apoptosis in human myeloid leukemia cells through the downregulation of HK-II mRNA expression mediated by reduction in c-Myc binding to HK-II gene intron, leading to the downregulation of HK-II protein. They further found that expression of proapoptotic protein Bad was inversely correlated with the expression level of HK-II in K562 stable cell lines treated with MAT (Figure 6) [69]. HK-II knockdown/overexpression promoted/inhibited MAT-induced apoptosis and growth inhibition in K562 myeloid leukemia cells, respectively.…”