Berberine exerts its antineoplastic effects by reversing the Warburg effect via downregulation of the Akt/mTOR/GLUT1 signaling pathway

Guo,Xiao-Hong; Jiang,Shui-Shan; Zhang,Li-Li; Hu,Jun; Edelbek,Dilda; Feng,Yu-Qi; Yang,Zi-Xian; Hu,Peng-Chao; Zhong,Hua; Yang,Guo-Hua; Yang,Fang

doi:10.3892/or.2021.8204

Berberine exerts its antineoplastic effects by reversing the Warburg effect via downregulation of the Akt/mTOR/GLUT1 signaling pathway

Authors:
- Xiao-Hong Guo
- Shui-Shan Jiang
- Li-Li Zhang
- Jun Hu
- Dilda Edelbek
- Yu-Qi Feng
- Zi-Xian Yang
- Peng-Chao Hu
- Hua Zhong
- Guo-Hua Yang
- Fang Yang
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Affiliations: Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China, Medical Security Office, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan University, Wuhan, Hubei 430071, P.R. China, Nursing Department, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Medical Genetics, School of Basic Medical Science, Demonstration Center for Experimental Basic Medicine Education, Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Oncology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Plant Sciences, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
Published online on: October 13, 2021 https://doi.org/10.3892/or.2021.8204
Article Number: 253
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glucose transporter 1 (GLUT1) plays a primary role in the glucose metabolism of cancer cells. However, to the best of our knowledge, there are currently no anticancer drugs that inhibit GLUT1 function. The present study aimed to investigate the antineoplastic activity of berberine (BBR), the main active ingredient in numerous Traditional Chinese medicinal herbs, on HepG2 and MCF7 cells. The results of Cell Counting Kit‑8 assay, colony formation assay and flow cytometry revealed that BBR effectively inhibited the proliferation of tumor cells, and induced G₂/M cell cycle arrest and apoptosis. Notably, the results of luminescence ATP detection assay and glucose uptake assay showed that BBR also significantly inhibited ATP synthesis and markedly decreased the glucose uptake ability, which suggested that the antitumor effect of BBR may occur via reversal of the Warburg effect. In addition, the results of reverse transcription‑quantitative PCR, western blotting and immunofluorescence staining indicated that BBR downregulated the protein expression levels of GLUT1, maintained the cytoplasmic internalization of GLUT1 and suppressed the Akt/mTOR signaling pathway in both HepG2 and MCF7 cell lines. Augmentation of Akt phosphorylation levels by the Akt activator, SC79, abolished the BBR‑induced decrease in ATP synthesis, glucose uptake, GLUT1 expression and cell proliferation, and reversed the proapoptotic effect of BBR. These findings indicated that the antineoplastic effect of BBR may involve the reversal of the Warburg effect by downregulating the Akt/mTOR/GLUT1 signaling pathway. Furthermore, the results of the co‑immunoprecipitation assay demonstrated that BBR increased the interaction between ubiquitin conjugating enzyme E2 I (Ubc9) and GLUT1, which suggested that Ubc9 may mediate the proteasomal degradation of GLUT1. On the other hand, BBR decreased the interaction between Gα‑interacting protein‑interacting protein at the C‑terminus (GIPC) and GLUT1, which suggested that the retention of GLUT1 in the cytoplasm may be achieved by inhibiting the interaction between GLUT1 and GIPC, thereby suppressing the glucose transporter function of GLUT1. The results of the present study provided a theoretical basis for the application of the Traditional Chinese medicine component, BBR, for cancer treatment.

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