Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231Funding This investigation was supported by deputy of research, Iran University of Medical Sciences, grant No. 960220631570.
Background Glucagon-like petide-1 (GLP-1) agonists such as liraglutide are widely employed in type 2 diabetes due to their glucose reducing properties and small risk of hypoglycemia. Recently, it has been shown that GLP-1agonists can inhibit breast cancer cells growth. Nonetheless, concerns are remained about liraglutide tumor promoting effects as stated by population studies.
Material and Methods We evaluated the effects liraglutide on proliferation of MDA-MB-231 cells by MTT assay and then ATP-binding cassette (ABC) transporters expressions assessed by Real time PCR. Statistical comparisons were made using one-way analysis of variance followed by a post hoc Dunnett test.
Results Here, we report that liraglutide can stimulate the growth of highly invasive triple negative cell line MDA-MB-231; which can be attributed to AMPK-dependent epithelial-mesenchymal transition (EMT) happening in MDA-MB-231 context. Toxicity effects were only observed with concentrations far above the serum liraglutide concentration. ATP-binding cassette (ABC) transporters expressions were upregulated, indicating the possible drug resistance and increased EMT.
Conclusion In conclusion, these results suggest that liraglutide should be used with caution in patients who are suffering or have the personal history of triple negative breast cancer. However, more detailed studies are required to deepen understanding of liraglutide consequences in triple negative breast cancer. ▶Graphical Abstract.
Key wordsliraglutide - Triple negative breast cancer (TNBC) - ATP- binding cassette (ABC) transporters - Glucagon-like petide-1 (GLP-1)
Eingereicht: 26. November 2020
Angenommen: 29. Dezember 2020
Artikel online veröffentlicht:
21. Januar 2021
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- 1 Noto H, Tsujimoto T, Sasazuki T. et al. Significantly increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis. Endocr Pract 2011; 17: 616-628
- 2 Tsilidis KK, Kasimis JC, Lopez DS. et al. Type 2 diabetes and cancer: Umbrella review of meta-analyses of observational studies. BMJ 2015; 350: g7607
- 3 Lipscombe LL, Fischer HD, Austin PC. et al. The association between diabetes and breast cancer stage at diagnosis: A population-based study. Breast Cancer Res Treat 2015; 150: 613-620
- 4 Calle EE, Rodriguez C, Walker-Thurmond K. et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625-1638
- 5 Davis AA, Kaklamani VG. Metabolic syndrome and triple-negative breast cancer: A new paradigm. Int J Breast Cancer 2012; 2012 809291
- 6 Nauck MA. Unraveling the science of incretin biology. Eur J Intern Med 2009; 20 Suppl 2 S303-S308
- 7 Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157
- 8 Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol 2012; 166: 27-41
- 9 Deacon CF, Nauck MA, Toft-Nielsen M. et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126-1131
- 10 Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother 2009; 43: 1433-1444
- 11 Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004; 145: 2653-2659
- 12 Ligumsky H, Wolf I, Israeli S. et al. The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat 2012; 132: 449-461
- 13 Fidan-Yaylali G, Dodurga Y, Secme M. et al. Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells. Tumour Biol 2016; 37: 2647-2653
- 14 Hicks BM, Yin H, Yu OH. et al. Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ 2016; 355: i5340
- 15 Bolen SD, Maruthur NM. Glucagon-like peptide-1 receptor agonists and risk of breast cancer. BMJ 2016; 355: i5519
- 16 Zhao W, Zhang X, Zhou Z. et al. Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression. Mol Med Rep 2018; 17: 5202-5212
- 17 Comsa S, Cimpean AM, Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer Res 2015; 35: 3147-3154
- 18 Korner M, Stockli M, Waser B. et al. GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J Nucl Med 2007; 48: 736-743
- 19 Krasner NM, Ido Y, Ruderman NB. et al. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One 2014; 9: e97554
- 20 Andreozzi F, Raciti GA, Nigro C. et al. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J Transl Med 2016; 14: 229
- 21 Faubert B, Vincent EE, Poffenberger MC. et al. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett 2015; 356 (2 Pt A): 165-170
- 22 Saxena M, Balaji SA, Deshpande N. et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J Cell Sci 2018; 131: jcs208314
- 23 Laderoute KR, Calaoagan JM, Chao WR. et al. 5′-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem 2014; 289: 22850-22864
- 24 Jacobsen LV, Flint A, Olsen AK. et al. Liraglutide in type 2 diabetes mellitus: Clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2016; 55: 657-672
- 25 Saxena M, Stephens MA, Pathak H. et al. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2011; 2: e179
- 26 Ding XW, Wu JH, Jiang CP. ABCG2: A potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci 2010; 86: 631-637
- 27 Mato E, Gonzalez C, Moral A. et al. ABCG2/BCRP gene expression is related to epithelial-mesenchymal transition inducer genes in a papillary thyroid carcinoma cell line (TPC-1). J Mol Endocrinol 2014; 52: 289-300