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Metabolic Phenotype Intricacies on Altered Glucose Metabolism of Breast Cancer Cells upon Glut-1 Inhibition and Mimic Hypoxia In Vitro

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Abstract

Breast cancer is the frequently diagnosed cancer and the leading cancer death among women. The growing tumour of the breast is composed of both normoxic and hypoxic cells, and the heterogeneity of tumour affects the targeted treatment strategies against breast cancer. The functional and therapeutic status of the Warburg effect is mostly recognized, and the genes involved in glycolysis have become a target for anticancer therapeutic strategies. Glut-1 is essential for basal glucose uptake among the glucose transporters and could act as a potential target for anticancer therapy. In the present study, we explored the alteration in the metabolic phenotype of SKBR-3 cells, representing HER-2 overexpressed breast cancer cell line, with Glut-1 inhibition by a synthetic small molecule inhibitor WZB117 in the presence or absence of cobalt chloride (CoCl2) induced biochemical hypoxia in vitro. We found that WZB117 and CoCl2 in combination could inhibit metabolic phenotype characteristics such as glucose uptake, cell migration, lactate and ATP production in SKBR-3 cells. Also, Glut-1 inhibition induced apoptosis and cell cycle arrest at the G0–G1 phase even under CoCl2-induced mimic hypoxia. Our findings suggest that Glut-1 inhibition by WZB117 could overcome the protective effect of CoCl2 mimic hypoxia by regulating glycolysis and altering the metabolic phenotype of breast cancer cells. The considering excellent efficacy and minimal toxicity suggest that WZB117 may be a promising anticancer drug to the current therapies.

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Funding

Author A.B.L. has received research support from University Grants Commission, Government of India (F.16–6(DEC.2016)/2017(NET)); UGC-Ref. No. 951/(OBC)(CSIR-UGC NET DEC.2016).

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Authors and Affiliations

  1. Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India

    Ajeesh Babu Littleflower, Gisha Rose Antony, Sulfath Thottungal Parambil & Lakshmi Subhadradevi

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  1. Ajeesh Babu Littleflower
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  2. Gisha Rose Antony
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  3. Sulfath Thottungal Parambil
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  4. Lakshmi Subhadradevi
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Contributions

A.B.L and L.S. contributed to the study conception and design. Experimentation, data collection, and analysis were performed by A.B.L. Flow cytometric analysis and microscopic imaging were assisted by S.T.P. and G.R.A. The first draft of the manuscript was written by A.B.L. Manuscript was revised and edited by L.S. All authors read and approved the final manuscript.

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Correspondence to Lakshmi Subhadradevi.

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Littleflower, A.B., Antony, G.R., Parambil, S.T. et al. Metabolic Phenotype Intricacies on Altered Glucose Metabolism of Breast Cancer Cells upon Glut-1 Inhibition and Mimic Hypoxia In Vitro. Appl Biochem Biotechnol 195, 5838–5854 (2023). https://doi.org/10.1007/s12010-023-04373-5

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