1. Academic Validation
  2. Flavonoid GL-V9 induces apoptosis and inhibits glycolysis of breast cancer via disrupting GSK-3β-modulated mitochondrial binding of HKII

Flavonoid GL-V9 induces apoptosis and inhibits glycolysis of breast cancer via disrupting GSK-3β-modulated mitochondrial binding of HKII

  • Free Radic Biol Med. 2020 Jan;146:119-129. doi: 10.1016/j.freeradbiomed.2019.10.413.
Yongjian Guo 1 Libin Wei 2 Yuxin Zhou 2 Na Lu 2 Xiaoqing Tang 1 Zhiyu Li 3 Xiaotang Wang 4
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 3 State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 4 Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA. Electronic address: wangx@fiu.edu.
Abstract

Energy metabolism plays important roles in the growth and survival of Cancer cells. Here, we find a newly synthesized flavonoid named GL-V9, which inhibits glycolysis and induces Apoptosis of human breast Cancer cell lines, and investigate the underlying mechanism. Results show that Hexokinase II (HKII) plays important roles in the Anticancer effects of GL-V9. GL-V9 not only downregulates the expression of HKII in MDA-MB-231 and MCF-7 cells, but also induces dissociation of HKII from voltage-dependent anion channel (VDAC) in mitochondria, resulting in glycolytic inhibition and mitochondrial-mediated Apoptosis. The dissociation of mitochondrial HKII is attributed to GSK-3β-induced phosphorylation of mitochondrial VDAC. Our in vivo experiments also show that GL-V9 significantly inhibits the growth of human breast Cancer due to activation of GSK-3β and inactivation of Akt. Thus, GL-V9 induces cytotoxicity in breast Cancer cells via disrupting the mitochondrial binding of HKII. Our works demonstrate the significance of metabolic regulators in Cancer growth and offer a fresh insight into the molecular basis for the development of GL-V9 as a candidate for breast carcinoma treatment.

Keywords

Apoptosis; GL-V9; GSK-3β; HKII; Mitochondria.

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