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Role of Insulin-Like Growth Factor Binding Protein-2 and Its Limited Proteolysis in Neuroblastoma Cell Proliferation: Modulation by Transforming Growth Factor-ß and Retinoic Acid¹

INSERM U.142, Hôpital Saint Antoine, 75571 Paris Cedex 12, France

Address all correspondence and requests for reprints to: Sylvie Babajko, INSERM U.142, Hôpital Saint Antoine, 184, rue du Faubourg St. Antoine, 75571 Paris Cedex 12, France.

Insulin-like growth factor (IGF) binding proteins (IGFBPs) modulate IGF action at cellular level through inhibition or, alternatively, potentiation, where their limited proteolysis is a contributory mechanism.

Under basal conditions, neuroblastoma cells secrete IGFs (essentially IGF-II), IGFBPs (IGFBP-4 and predominantly IGFBP-2 that is partially proteolysed), and proteases, including tissue-type plasminogen (PLG) activator, whose activity is inhibited by PLG activator inhibitor-1.

Neuroblastoma cells were used to investigate the influence of the plasmin system, transforming growth factor-ß and retinoic acid on cell growth and the IGF system. In cells treated with 5 µg/ml PLG, proliferation was stimulated, an effect that was inhibited in the presence of either IR-3 (which blocks the type 1 IGF receptor) or anti-IGF-II antibodies. There was a parallel increase in IGFBP-2 proteolysis, which resulted in a 5-fold loss of affinity for IGF-II.

In the presence of 1 ng/ml transforming growth factor-ß, PLG-induced mitogenesis and IGFBP-2 proteolysis were reduced, and Northern blot analysis revealed increased PLG activator inhibitor-1 mRNA. Conversely, with 2 µM retinoic acid, the mitogenic effect of PLG, IGFBP-2 proteolysis, and tissue-type PLG activator mRNAs were increased.

Therefore, IGF-II mediates autocrine proliferation in neuroblastoma cells under the control of IGFBPs secreted by the cells, its bioavailability being enhanced as a result of plasmin-induced IGFBP-2 proteolysis.

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