Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells

Fidan-Yaylalı, Güzin; Dodurga, Yavuz; Seçme, Mücahit; Elmas, Levent

doi:10.1007/s13277-015-4104-9

Cited by 18 publications

(10 citation statements)

References 28 publications

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“…Breast cancer is among the most common types of malignant tumors that affect women, according to statistics from developed countries in North America and Europe ( 30 ). Several studies have reported that breast cancer incidence and mortality risk are closely associated with metabolic disease ( 31 – 33 ). The present study reported that liraglutide, which is widely employed for hypoglycemic treatment, also exhibited an inhibitory effect on the proliferation of MCF-7 cells and promoted apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression

et al. 2018

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The use of glucagon-like peptide-1 analogues, such as liraglutide, as hypoglycemic drugs has been widely employed in clinical practice. Liraglutide is reported to exert potential anti-breast cancer effects, however the specific mechanisms of this action remain unknown. In the present study, MCF-7 human breast cancer cells were cultured in vitro and treated with various concentrations of liraglutide. Cell Counting Kit-8, colony formation and flow cytometry assays were performed to determine the proliferation and apoptosis of cells following treatment. Furthermore, reverse transcription-quantitative polymerase chain reaction was employed to measure the expression level of microRNA (miRNA/miR)-27a. In addition, miR-27a mimics, inhibitors and negative controls were transfected into MCF-7 cells and the proliferation and apoptosis of cells following transfection was subsequently determined. Western blotting was performed to detect alterations in the protein expression of AMP-activated protein kinase catalytic subunit α2 (AMPKα2), proliferating cell nuclear antigen and cleaved-caspase-3 following treatments. The results demonstrated that, following treatment with liraglutide, the proliferation of MCF-7 cells was reduced and the apoptosis was increased, compared with the control group; this effect was increased with increasing concentrations of liraglutide. In addition, liraglutide treatment downregulated miR-27a expression in MCF-7 cells. While the overexpression of miR-27a promoted cell proliferation and inhibited apoptosis, knockdown of endogenous miR-27a inhibited cell proliferation and promoted apoptosis in MCF-7 cells. Furthermore, the expression of AMPKα2 protein in the group transfected with miR-27a mimics was decreased, while it was increased in MCF-7 cells transfected with miR-27a inhibitors. In conclusion, liraglutide may have a role in the inhibition of proliferation and promotion of apoptosis in MCF-7 cells. Concerning the mechanism of these effects, liraglutide may inhibit miR-27a expression, which subsequently increases the expression of AMPKα2 protein. The present study provides an experimental basis for the clinical treatment strategies of T2DM patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression

et al. 2018

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“…Overall, the scarce in vitro data limit our understanding of the role of incretins and cancer. Although the mechanisms of action of GLP-1 analogs are yet to be elucidated, GLP-1 analogs have been shown to influence cancer cells by altering proliferation, apoptosis, ECM remodeling and the response to chemotherapy ( 17 , 18 , 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…The role of GLP-1 analogs on cancer cell growth and invasion both in vitro and in vivo is yet to be elucidated. Incretins have shown to inhibit growth and enhance apoptosis of cancer cells through inhibition of the PI3K/Akt pathway for some cell lines of breast ( 17 ), colon cancer ( 18 ) and ovarian cancer ( 19 ). Thus, understating of the role of GLP-1 analogs has important clinical implication in the design of novel anti-cancer therapies emphasizing the potential benefits of combining both incretins with chemotherapy-cytostatic drugs.…”

Section: Introductionmentioning

confidence: 99%

Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells

Kosowska

Gallego‐Colon

Garczorz

et al. 2017

Endocrine Connections

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Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.

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“…Several evidences obtained from in vitro studies indicate that GLP-1 agonists can exert growth inhibition effects on breast cancer lines [12,13,16]. However, these investigations were mostly done by either exenatide (exendine-4), the first widely used GLP-1 agonist, or on the MCF-7 cell line, which represents a poorly aggressive and non-invasive phenotype [17] of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Incretins have been shown to enhance cell proliferation in several tissues including pancreas, central nervous and gastrointestinal systems [11] and as a result increased risk of cancer development can be assumed. On the other hand, GLP-1 agonists have been found to be toxic for breast cancer cells [12,13]. In most of these studies the oldest FDA approved GLP-1 agonist, exenatide, has been used.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells

Cited by 18 publications

References 28 publications

Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression

Liraglutide inhibits the proliferation and promotes the apoptosis of MCF-7 human breast cancer cells through downregulation of microRNA-27a expression

Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells

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

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