Tumor Biology

, Volume 37, Issue 2, pp 2647–2653 | Cite as

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

  • Güzin Fidan-Yaylalı
  • Yavuz Dodurga
  • Mücahit Seçme
  • Levent Elmas
Original Article

Abstract

Exendin-4 is a GLP-1 analog used for the treatment of type 2 diabetes mellitus in its synthetic form. As women with diabetes have higher breast cancer incidence and mortality, we examined the effect of the incretin drug exendin-4 on breast cancer cells. The aim of the study is to investigate anticancer mechanism of exendin-4 in MCF-7 breast cancer cells. Cytotoxic effects of exendin-4 were determined by XTT assay. IC50 dose in MCF-7 cells were detected as 5 μM at 48th hour. Gene messenger RNA (mRNA) expressions were evaluated by real-time PCR. According to results, caspase-9, Akt, and MMP2 expression was reduced in dose group cells, compared with the control group cells. p53, caspase-3, caspase-8, caspase-10, BID, DR4, DR5, FADD, TRADD, PARP, PTEN, PUMA, NOXA, APAF, TIMP1, and TIMP2 expression was increased in dose group cells, compared with the control group cells. Effects of exendin-4 on cell invasion, colony formation, and cell migration were detected by Matrigel chamber, colony formation assay, and wound-healing assay, respectively. To conclude, it is thought that exendin-4 demonstrates anticarcinogenesis activity by effecting apoptosis, invasion, migration, and colony formation in MCF-7 cells. Exendin-4 may be a therapeutic agent for treatment of breast cancer as single or in combination with other agents. More detailed researches are required to define the pathways of GLP-1 effect on breast cancer cells because of the molecular biology of breast cancer that involves a complex network of interconnected signaling pathways that have role in cell growth, survival, and cell invasion.

Keywords

Exendin-4 Glucagon-like peptide Breast cancer Diabetes 

Abbreviations

DM

Diabetes mellitus

GLP-1

Glucagon-like peptide-1

GPCR

G protein-coupled receptor

IGF-1

Insulin-like growth factor 1

XTT

2,3-Bis-(2-Metoksi-4-nitro-5-sülfofenil)-2H-tetrazolium-5-carboxanilide

Notes

Compliance with ethical standards

Conflicts of interest

None

Ethics approval and consent to participate

There is no need to take ethical approval and informed consent for this study.

References

  1. 1.
    Noto H, Tsujimoto T, Sasazuki T, Noda M. Significantly increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Endocr Pract. 2011;17(4):616–28.CrossRefPubMedGoogle Scholar
  2. 2.
    Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA. 2008;300(23):2754–64.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Peairs KS, Barone BB, Snyder CF, Yeh HC, Stein KB, Derr RL, et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol. 2011;29(1):40–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6:103–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Eliassen AH, Tworoger SS, Mantzoros CS, Pollak MN, Hankinson SE. Circulating insulin and C-peptide levels and risk of breast cancer among predominately premenopausal women. Cancer Epidemiol Biomarkers Prev. 2007;16:161–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Schernhammer ES, Holly JM, Pollak MN, Hankinson SE. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14:699–704.CrossRefPubMedGoogle Scholar
  7. 7.
    Wolf I, Sadetzki S, Gluck I, Oberman B, Ben-David M, Papa MZ, et al. Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. Eur J Cancer. 2006;42:1077–82.CrossRefPubMedGoogle Scholar
  8. 8.
    Yee D. Targeting insulin-like growth factor pathways. Br J Cancer. 2006;94:465–8.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A, et al. The peptidehormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat. 2012;132:449–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–57.CrossRefPubMedGoogle Scholar
  11. 11.
    Dufayet de la Tour D, Halvorsen T, Demeterco C, Tyrberg B, Itkin-Ansari P, Loy M, et al. {beta}-Cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol. 2001;15:476–83.Google Scholar
  12. 12.
    Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–36.CrossRefPubMedGoogle Scholar
  13. 13.
    Idris I, Patiag D, Gray S, Donnelly R. Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: contrasting effects of GLP-1. Biochem Pharmacol. 2002;63:993–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, et al. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes. 2007;56(6):1671–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62:173–81.PubMedGoogle Scholar
  16. 16.
    Luciani P, Deledda C, Benvenuti S, Squecco R, Cellai I, Fibbi B, et al. Exendin 4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells. PLoS One. 2013;22:8(8).Google Scholar
  17. 17.
    Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology. 2011;152:3362–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Mikhail N. Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes. Curr Drug Saf. 2011;6:304–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Nomiyama T, Kawanami T, Irie S, Hamaguchi Y, Terawaki Y, Murase K, et al. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes. 2014;63(11):3891–905.CrossRefPubMedGoogle Scholar
  22. 22.
    Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, et al. Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies. J Clin Endocrinol Metab. 2007;92:1041–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 2010;70:741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Joung KH, Jeong JW, Ku BJ. The association between type 2 diabetes mellitus and women cancer: the epidemiological evidences and putative mechanisms. Biomed Res Int. 2015;2015:920618.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–13.CrossRefPubMedGoogle Scholar
  26. 26.
    Toft-Nielsen M-B, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion. Diabetes. 2003;52:380–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ, et al. Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab. 2009;95(2):872–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Güzin Fidan-Yaylalı
    • 1
  • Yavuz Dodurga
    • 2
  • Mücahit Seçme
    • 2
  • Levent Elmas
    • 2
  1. 1.Department of Endocrinology and Metabolic Diseases, Faculty of MedicinePamukkale UniversityDenizliTurkey
  2. 2.Department of Medical Biology and Genetics, Faculty of MedicinePamukkale UniversityDenizliTurkey

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