The in vitro effect of the diabetes-associated markers insulin, leptin and oxidative stress on cellular characteristics promoting breast cancer progression is GLUT1-dependent

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Silva, C (Author) Other; Andrade, N (Author) Other; guimaraes, jt (Author) FMUP; Patricio, E (Author) Other; Martel, F (Author) FMUP

Journal

Title: European Journal of Pharmacology

Vol. 898

ISSN: 0014-2999

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 16 Citations

Other information

Authenticus ID: P-00T-KXJ

DOI: 10.1016/j.ejphar.2021.173980

Abstract (EN): Obesity and type 2 diabetes mellitus (T2DM) associate with increased incidence and mortality from many cancers, including breast cancer. The mechanisms involved in this relation remain poorly understood. Our study aimed to investigate the in vitro effect of high levels of glucose, insulin, leptin, TNF-alpha, INF-gamma and oxidative stress (induced with tert-butylhydroperoxide (TBH)), which are associated with T2DM, upon glucose uptake by breast cancer (MCF-7 and MDA-MB-231) and non-cancer (MCF-12A) cells and to correlate this effect with their effects upon cellular characteristics associated with cancer progression (cell proliferation, viability, migration, angiogenesis and apoptosis). H-3-DG uptake was markedly inhibited by a selective GLUT1 inhibitor (BAY-876) in all cell lines, proving that H-3-DG uptake is mainly GLUT1-mediated. TBH (2.5 mu M), insulin (50 nM), leptin (500 ng/ml) and INF-y (100 ng/ml) stimulate GLUT1-mediated H-3-DG (1 mM) uptake by both ER-positive and triple-negative breast cancer cell lines. TBH and leptin, but not insulin and INF-gamma, increase GLUT1 mRNA levels. Insulin and leptin (in both ER-positive and triple-negative breast cancer cell lines) and TBH (in the triple-negative cell line) have a proproliferative effect and leptin possesses a cytoprotective effect in both breast cancer cell lines that can contribute to cancer progression. The effects of TBH, insulin, leptin and INF-gamma upon breast cancer cell proliferation and viability are GLUT1-dependent. In conclusion, T2DM-associated characteristics induce changes in GLUT1-mediated glucose uptake that can contribute to cancer progression. Moreover, we conclude that BAY-876 can be a strong candidate for development of a new effective anticancer agent against breast cancer.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13