Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231

Abstract

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.

GLP-1 receptor agonist as an effective treatment for breast cancer-related lymphedema: a case report

“…In the human estrogen receptorpositive MCF7 breast cancer cell line, GLP-1RA have consistently been reported to have anti-proliferative and pro-apoptotic effects (50)(51)(52)(53). In contrast, in the MDA-MB-231 TNBC cell line, the GLP1-RA liraglutide was found to stimulate cell growth in vitro, but exendin-4 reduced the proliferation (53)(54)(55). In vivo, liraglutide was also reported to accelerate the growth of murine 4T1 cells in a syngeneic model (55), but exendin-4 inhibited the growth of MDA-MB-231 and MDA-MB-468 TNBC xenografts (53).…”

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“…43 According to another study, depending on the cell population concentration, liraglutide could be both a stimulator and an inhibitor of MDA-MB-231 cell proliferation. 44 Moreover, researchers have indicated that DPP-4 signaling can promote epidermal growth factor-induced epithelial cell transformation and mammary tumorigenesis via the induction of peptidylpropyl cis-trans isomerase 1 expression, suggesting that sitagliptin as a DPP-4I could be useful for the treatment of breast tumors in patients with T2DM. 45 On the contrary, cell lines analysis suggested that DPP-4 inhibition could accelerate BC metastasis by inducing epithelial-mesenchymal transition through C-X-C motif chemokine 12/C-X-C receptor4 (CXCL12/CXCR4)mediated mammalian target of rapamycin activation and promote chemoresistance in BC cells.…”

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“…Liraglutide restricted the expression of microRNA 27a and in turn promoted the expression of the AMPKα2 protein in MCF-7 cells [ 199 ]. However, this agent promoted the proliferation of highly invasive MDA-MB-231 cells which possessed AMPK-dependent EMT properties [ 200 ]. Alteration of the ATP/AMP ratio is a common mechanism that some modulators apply to activate AMPK [ 201 ].…”