Skip to main content
Top
Published in: Journal of Diabetes & Metabolic Disorders 1/2021

01-06-2021 | Breast Cancer | Research article

The rate of aerobic glycolysis is a pivotal regulator of tumor progression

Authors: Mohammad Erfan Zare, Atefeh Nasir Kansestani, Shahrooz Hemmati, Kamran Mansouri, Asad Vaisi-Raygani

Published in: Journal of Diabetes & Metabolic Disorders | Issue 1/2021

Login to get access

Abstract

Purpose

Cancer cells depend on glucose metabolism via exclusive glycolysis pathway is named Aerobic glycolysis or Warburg effect. The aim of this study was investigation of different glucose accessibility conditions on the rate of Warburg effect and its impact on Hypoxia inducible factors-1 α (HIF-1 α)/vascular endothelium growth factor (VEGF) pathway in breast cancer cells lines.

Methods

MDA-MB-231 (Warburg phenomenon) and MCF-7 (oxidative) cell lines were cultured in DMEM and exposed to three different glucose accessibility medium for 48 h (5.5 mM as normal glucose (NG), 25 mM as high glucose (HG) and 2-Deoxyglucose (2-DG) as restricted glucose accessibility). Glucose uptake, intra/extracellular lactate and pyruvate, HIF-1α accumulation and vascular endothelium growth factor (VEGF) expression were evaluated by standard methods.

Results

Our results showed in NG condition both of cell lines produce lactate, but it was higher in MDA-MB-231. HG condition increased extracellular lactate in both cell lines especially in MCF-7 cells whereas intracellular lactate and pyruvate raised only in MCF-7. 2-DG decreased extracellular and intracellular lactate and pyruvate in both cell lines especially in MDA-MB-231. HIF-1α accumulation was detectable in NG condition in both cell lines. HG condition increased HIF-1α accumulation in MCF-7 cells but not in MDA-MB-231 and 2-DG decreased it in both call lines, especially in MDA-MB-231. Expression of VEGF had similar pattern with HIF-1α in different conditions.

Conclusions

Our findings revealed the rate of Warburg effect is an important indicator for tumor promotion and invasion due to its impacts on important transcription factors like HIF-1α.
Literature
1.
go back to reference Kim J, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–30.CrossRef Kim J, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–30.CrossRef
2.
go back to reference Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors. Neoplasia. 2005;7:324–30.CrossRef Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors. Neoplasia. 2005;7:324–30.CrossRef
3.
go back to reference Sakamoto T, Niiya D, Seiki M. Targeting the Warburg effect that arises in tumor cells expressing membrane type-1 matrix metalloproteinase. J Biol Chem. 2011;286:14691–704.CrossRef Sakamoto T, Niiya D, Seiki M. Targeting the Warburg effect that arises in tumor cells expressing membrane type-1 matrix metalloproteinase. J Biol Chem. 2011;286:14691–704.CrossRef
4.
go back to reference Xu R, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65:613–21.PubMed Xu R, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65:613–21.PubMed
5.
go back to reference Cheng S, Yang Y, Ting K, Wen S-Y, Viswanadha VP, Huang C, et al. Lactate dehydrogenase downregulation mediates the inhibitory effect of diallyl trisulfide on proliferation, metastasis, and invasion in triple-negative breast cancer. Environ Toxicol. 2017;32:1390–8.CrossRef Cheng S, Yang Y, Ting K, Wen S-Y, Viswanadha VP, Huang C, et al. Lactate dehydrogenase downregulation mediates the inhibitory effect of diallyl trisulfide on proliferation, metastasis, and invasion in triple-negative breast cancer. Environ Toxicol. 2017;32:1390–8.CrossRef
6.
go back to reference Gupta C, Kaur J, Tikoo K. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions. Exp Cell Res. 2014;324:75–83.CrossRef Gupta C, Kaur J, Tikoo K. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions. Exp Cell Res. 2014;324:75–83.CrossRef
7.
go back to reference Wahdan-Alaswad R, Fan Z, Edgerton SM, Liu B, Deng X-S, Arnadottir SS, et al. Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle. 2013;12:3759–69.CrossRef Wahdan-Alaswad R, Fan Z, Edgerton SM, Liu B, Deng X-S, Arnadottir SS, et al. Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle. 2013;12:3759–69.CrossRef
8.
go back to reference Kunhiraman H, Edatt L, Thekkeveedu S, Poyyakkara A, Raveendran V, Kiran MS, et al. 2-Deoxy glucose modulates expression and biological activity of VEGF in a SIRT-1 dependent mechanism. J Cell Biochem. 2017;118:252–62.CrossRef Kunhiraman H, Edatt L, Thekkeveedu S, Poyyakkara A, Raveendran V, Kiran MS, et al. 2-Deoxy glucose modulates expression and biological activity of VEGF in a SIRT-1 dependent mechanism. J Cell Biochem. 2017;118:252–62.CrossRef
9.
go back to reference Wu Y, Sarkissyan M, Mcghee E, Lee S, Vadgama JV. Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing. Breast Cancer Res Treat. 2015;151:529–39.CrossRef Wu Y, Sarkissyan M, Mcghee E, Lee S, Vadgama JV. Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing. Breast Cancer Res Treat. 2015;151:529–39.CrossRef
10.
go back to reference Villarreal-Garza C, Shaw-Dulin R, Lara-Medina F, Bacon L, Rivera D, Urzua L, et al. Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. Exp Diabetes Res. 2012;2012:732027.CrossRef Villarreal-Garza C, Shaw-Dulin R, Lara-Medina F, Bacon L, Rivera D, Urzua L, et al. Impact of diabetes and hyperglycemia on survival in advanced breast cancer patients. Exp Diabetes Res. 2012;2012:732027.CrossRef
11.
go back to reference Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.CrossRef Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.CrossRef
12.
13.
go back to reference Ziello JE, Jovin IS, Huang Y. Hypoxia-inducible factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80:51–60.PubMedPubMedCentral Ziello JE, Jovin IS, Huang Y. Hypoxia-inducible factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80:51–60.PubMedPubMedCentral
14.
go back to reference Dehne N, Hintereder G, Brüne B. High glucose concentrations attenuate hypoxia-inducible factor-1α expression and signaling in non-tumor cells. Exp Cell Res. 2010;316:1179–89.CrossRef Dehne N, Hintereder G, Brüne B. High glucose concentrations attenuate hypoxia-inducible factor-1α expression and signaling in non-tumor cells. Exp Cell Res. 2010;316:1179–89.CrossRef
15.
go back to reference Duan W, Shen X, Lei J, Xu Q, Yu Y, Li R, et al. Hyperglycemia, a neglected factor during cancer progression. Biomed Res Int. 2014;2014:461917.CrossRef Duan W, Shen X, Lei J, Xu Q, Yu Y, Li R, et al. Hyperglycemia, a neglected factor during cancer progression. Biomed Res Int. 2014;2014:461917.CrossRef
16.
go back to reference Van Hée VF, Pérez-Escuredo J, Cacace A, Copetti T, Sonveaux P. Lactate does not activate NF-κB in oxidative tumor cells. Front Pharmacol. 2015;6:228.PubMed Van Hée VF, Pérez-Escuredo J, Cacace A, Copetti T, Sonveaux P. Lactate does not activate NF-κB in oxidative tumor cells. Front Pharmacol. 2015;6:228.PubMed
17.
go back to reference Gupta C, Tikoo K. High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells. J Mol Endocrinol. 2013;51:119–29.CrossRef Gupta C, Tikoo K. High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells. J Mol Endocrinol. 2013;51:119–29.CrossRef
18.
go back to reference Lunetti P, Di Giacomo M, Vergara D, De Domenico S, Maffia M, Zara V, et al. Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes. FEBS J. 2019;286:688–709.CrossRef Lunetti P, Di Giacomo M, Vergara D, De Domenico S, Maffia M, Zara V, et al. Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes. FEBS J. 2019;286:688–709.CrossRef
19.
go back to reference Nasir Kansestani A, Mansouri K, Hemmati S, Zare ME, Moatafaei A. High glucose-reduced apoptosis in human breast Cancer cells is mediated by activation of NF-κB. Iran J Allergy, Asthma Immunol. 2019;18:153–62. Nasir Kansestani A, Mansouri K, Hemmati S, Zare ME, Moatafaei A. High glucose-reduced apoptosis in human breast Cancer cells is mediated by activation of NF-κB. Iran J Allergy, Asthma Immunol. 2019;18:153–62.
20.
go back to reference Flores-López LA, Martínez-Hernández MG, Viedma-Rodríguez R, Díaz-Flores M, Baiza-Gutman LA. High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol. 2016;39:365–78.CrossRef Flores-López LA, Martínez-Hernández MG, Viedma-Rodríguez R, Díaz-Flores M, Baiza-Gutman LA. High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol. 2016;39:365–78.CrossRef
21.
go back to reference Zeng L, Biernacka KM, Holly JMP, Jarrett C, Morrison AA, Morgan A, et al. Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase. Endocr Relat Cancer. 2010;17:539–51.CrossRef Zeng L, Biernacka KM, Holly JMP, Jarrett C, Morrison AA, Morgan A, et al. Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase. Endocr Relat Cancer. 2010;17:539–51.CrossRef
22.
go back to reference Guppy M, Leedman P, XinLin ZU, Russell V. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002;364:309–15.CrossRef Guppy M, Leedman P, XinLin ZU, Russell V. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002;364:309–15.CrossRef
23.
go back to reference Hussien R, Brooks GA. Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines. Physiol Genomics. 2011;43:255–64.CrossRef Hussien R, Brooks GA. Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines. Physiol Genomics. 2011;43:255–64.CrossRef
24.
go back to reference Kaufman RJ, Scheuner D, Schröder M, Shen X, Lee K, Liu CY, et al. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol. 2002;3:411–21.CrossRef Kaufman RJ, Scheuner D, Schröder M, Shen X, Lee K, Liu CY, et al. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol. 2002;3:411–21.CrossRef
25.
go back to reference Papathanassiu AE, MacDonald NJ, Emlet DR, Vu HA. Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo. Cell Stress Chaperones. 2011;16:181–93.CrossRef Papathanassiu AE, MacDonald NJ, Emlet DR, Vu HA. Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo. Cell Stress Chaperones. 2011;16:181–93.CrossRef
26.
go back to reference Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 2002;277:23111–5.CrossRef Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 2002;277:23111–5.CrossRef
27.
go back to reference Adham SAI, Al Rawahi H, Habib S, Al Moundhri MS, Viloria-Petit A, Coomber BL. Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules. PLoS One. 2014;9:e113103.CrossRef Adham SAI, Al Rawahi H, Habib S, Al Moundhri MS, Viloria-Petit A, Coomber BL. Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules. PLoS One. 2014;9:e113103.CrossRef
28.
go back to reference De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7:e46571.CrossRef De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7:e46571.CrossRef
Metadata
Title
The rate of aerobic glycolysis is a pivotal regulator of tumor progression
Authors
Mohammad Erfan Zare
Atefeh Nasir Kansestani
Shahrooz Hemmati
Kamran Mansouri
Asad Vaisi-Raygani
Publication date
01-06-2021
Publisher
Springer International Publishing
Published in
Journal of Diabetes & Metabolic Disorders / Issue 1/2021
Electronic ISSN: 2251-6581
DOI
https://doi.org/10.1007/s40200-021-00774-7

Other articles of this Issue 1/2021

Journal of Diabetes & Metabolic Disorders 1/2021 Go to the issue