Insulin inhibits platelet-derived growth factor-induced cell proliferation.
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.
Cirri
P
P
Dipartimento di Scienze Biochimiche, Università di Firenze, 50134 Firenze, Italy.
Taddei
M L
ML
Chiarugi
P
P
Buricchi
F
F
Caselli
A
A
Paoli
P
P
Giannoni
E
E
Camici
G
G
Manao
G
G
Raugei
G
G
Ramponi
G
G
D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D002450:Cell Communication; D002460:Cell Line; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015536:Down-Regulation; D004705:Endocytosis; D005840:Gentian Violet / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008938:Mitosis; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013936:Thymidine / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000891:Anti-Infective Agents, Local; D016895:Culture Media, Serum-Free; D007328:Insulin; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D014443:Tyrosine; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; D005840:Gentian Violet; D013936:Thymidine