Diabetogenic glucose and insulin concentrations modulate transcriptom and protein levels involved in tumour cell migration, adhesion and proliferation

BACKGROUND: During the last decade, epidemiological studies uncovered the tremendous impact of metabolic syndrome/diabetes mellitus type 2 (DM T2) as risk factors of the progression of cancer. Therefore, we studied the impact of diabetogenic glucose and insulin concentrations on the activities of tumour cells, because little is known about how high glucose and insulin levels are influencing gene activities causing changes in the signal cascade activities with respect to kinases involved in the proliferation and migration of cancer cells. METHODS: To address this question we analysed the activity of more than 400 gene signatures related to (i) cell cycle, (ii) cell movement as well as (iii) signal transduction. We examined transcriptoms of kinases (PKC alpha, PI3K), cadherins (E-, N- VE-), integrins and cyclins by comparing physiological (5.5 mM) vs diabetogenic (11 mM) glucose concentrations (without and with insulin). RESULTS: Proliferation assays revealed that high levels of glucose (11 mM) and insulin (100 ng ml(-1)) did promote the proliferation of the tumour cell lines HT29, SW480, MCF-7, MDA MB468, PC3 and T24. Using a 3D-migration assay, we have shown that high glucose concentrations caused increased motility rates of the tumour cells. The increase in migratory activity at high glucose and insulin concentrations was mediated by an activation of PI3K, PKC alpha and MLCK, as figured out by the pharmacological inhibitors wortmannin, Go6976 and ML-7. CONCLUSION: We present molecular and functional data, which could help to understand how hyperglycaemia and hyperinsulinemia might trigger tumour cell proliferation and motility in patients, too. British Journal of Cancer (2011) 104, 345-352. doi: 10.1038/sj.bjc.6606050 www.bjcancer.com Published online 21 December 2010 (C) 2011 Cancer Research UK