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Vol. 16, Issue 1, 73-83, January 2005

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Insulin Inhibits Platelet-derived Growth Factor-induced Cell Proliferation

Dipartimento di Scienze Biochimiche, Università di Firenze, 50134 Firenze, Italy

Submitted January 8, 2004; Revised October 12, 2004; Accepted October 26, 2004
Monitoring Editor: Carl-Henrik Heldin

Cellular behavior can be considered to be the result of a very complex spatial and temporal integration of intracellular and extracellular signals. These signals arise from serum-soluble factors as well as from cell–substrate or cell–cell interactions. The current approach in mitogenesis studies is generally to analyze the effect of a single growth factor on serum-starved cells. In this context, a metabolic hormone such as insulin is found to be a mitogenic agent in many cellular types. In the present study, we have considered the effect of insulin stimulation in platelet-derived growth factor (PDGF)-activated NIH-3T3 and C2C12 cells. Our results show that insulin is able to inhibit strongly both NIH-3T3 and C2C12 cell growth induced by PDGF, one of the most powerful mitotic agents for these cell types. This inhibitory effect of insulin is due primarily to a premature down-regulation of the PDGF receptor. Thus, when NIH-3T3 or C2C12 cells are stimulated with both PDGF and insulin, we observe a decrease in PDGF receptor phosphorylation with respect to cells treated with PDGF alone. In particular, we find that costimulation with insulin leads to a reduced production of H₂O₂ with respect to cell stimulation with PDGF alone. The relative low concentration of H₂O₂ in PDGF/insulin-costimulated cell leads to a limited down-regulation of protein tyrosine phosphatases, and, consequently, to a reduced PDGF receptor phosphorylation efficiency. The latter is very likely to be responsible for the insulin-dependent inhibition of PDGF-receptor mitogenic signaling.

Abbreviations used: ERK, extracellular signal-regulated kinase; IR, insulin receptor; PDGF, platelet-derived growth factor, PDGF-R, platelet-derived growth factor-receptor; PI-3K, phosphatidylinositol 3-phosphate kinase; PTB, protein tyrosine-binding; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; ROS, reactive oxygen species; SH2, Src homology-2.

^* Corresponding author. E-mail address: ramponi{at}scibio.unifi.it.