2. Academic Validation
  3. Betulinic acid suppresses breast cancer aerobic glycolysis via caveolin-1/NF-κB/c-Myc pathway

Betulinic acid suppresses breast cancer aerobic glycolysis via caveolin-1/NF-κB/c-Myc pathway

  • Biochem Pharmacol. 2019 Mar;161:149-162. doi: 10.1016/j.bcp.2019.01.016.
Lin Jiao 1,  Shengqi Wang 2,  Yifeng Zheng 2,  Neng Wang 3,  Bowen Yang 4,  Dongmei Wang 5,  Depo Yang 5,  Wenjie Mei 6,  Zhimin Zhao 7,  Zhiyu Wang 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China; Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 2 Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 3 Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 4 Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
  • 5 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
  • 7 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address: zhaozhm2@mail.sysu.edu.cn.
  • 8 Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: wangzhiyu@gzucm.edu.cn.
PMID: 30684465 DOI: 10.1016/j.bcp.2019.01.016
Abstract

Emerging evidence has suggested that targeting glycolysis may be a promising strategy for Cancer treatment. Betulinic acid (BA) is a natural pentacyclic terpene that has been reported to be active in inhibiting various malignancies. Here, we showed that BA could inhibit aerobic glycolysis activity in breast Cancer cell lines MCF-7 and MDA-MB-231 by hampering lactate production, glucose uptake and extracellular acidification rate (ECAR), as well as suppressing aerobic glycolysis-related proteins including c-Myc, Lactate Dehydrogenase A (LDH-A) and p-PDK1/PDK1 (pyruvate dehydrogenase kinase 1). Mechanistic studies validated Caveolin-1 (Cav-1) as one of key targets of BA in suppressing aerobic glycolysis, as BA administration resulted in Cav-1 upregulation, whereas silencing Cav-1 abrogated the inhibitory effect of BA on aerobic glycolysis. Further investigations demonstrated that BA suppressed aerobic glycolysis in breast Cancer cells by regulating the Cav-1/NF-κB/c-Myc pathway. More meaningfully, BA significantly inhibited breast Cancer growth and glycolytic activity in both the transgenic MMTV-PyVT+/- breast Cancer spontaneous model and the zebrafish breast Cancer xenotransplantation model without any detectable side effects in vivo. Taken together, our study sheds novel insights into BA as a promising candidate drug for suppressing aerobic glycolysis, highlighting Cav-1 as a potential molecular target of BA and aerobic glycolysis regulation.

Keywords

Aerobic glycolysis; Betulinic acid; Breast cancer; Caveolin-1; NF-κB/c-Myc.

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