tailieunhanh - Báo cáo khoa học: Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system

The mechanism behind the growth-promoting effect of insulin is a subject of debate. Employing RT4 bladder cancer cells, we examined the cross-talk between insulin and the epidermal growth factor system. We found that insulin induced a time- and dose-dependent (25–1000 nmolÆL )1 insulin) increase in mRNA expression of three ligands from the epidermal growth factor system. | ỊFEBS Journal Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system Dorthe Ornskov Ebba Nexo and Boe S. Sorensen Department of ClinicalBiochemistry Aarhus Sygehus University Hospital in Aarhus Denmark Keywords bladder cancer EGF-system insulin proliferation Correspondence B. S. Sorensen Department of Clinical Biochemistry NBG AS Aarhus University Hospital Norrebrogade 44 8000 Aarhus C Denmark Fax 45 89493060 Tel 45 89493048 E-mail boess@ Received 14 March 2006 revised 6 September 2006 accepted 16 October 2006 doi The mechanism behind the growth-promoting effect of insulin is a subject of debate. Employing RT4 bladder cancer cells we examined the cross-talk between insulin and the epidermal growth factor system. We found that insulin induced a time- and dose-dependent 25-1000 nmol L-1 insulin increase in mRNA expression of three ligands from the epidermal growth factor system. Times for peak increase and fold increase after incubation with 250 nmol L-1 insulin were as follows heparin-binding epidermal growth factor-like growth factor h P epiregulin 3 h 14-fold P and amphiregulin 3 h 12-fold P . Induction of heparin-binding epidermal growth factor-like growth factor and amphi-regulin was verified at the protein level. We demonstrate that incubation of RT4 bladder cancer cells for 24 h with 250 nmol L-1 insulin increases proliferation by 43 P as compared to untreated cells. At the same time phosphorylation and thereby activation of the epidermal growth factor receptor HER1 was observed. Both phosphorylation and insulin-induced proliferation were almost completely inhibited by the HER1 inhibitor Iressa P . This shows that insulin leads to activation of HER1 and that HER1 plays an essential role in mediating the growth-promoting effect of insulin. Iressa inhibited not only the activation of HER1 caused by insulin but