Signals transduced via insulin-like growth factor I receptor (IGF_R) mediate resistance to retinoic acid-induced cell growth arrest in a human neuroblastoma cell line

Retinoic Acid (RA) has been shown to control growth and induce differentiation in a number of human neuroblastoma (NB) cell lines. However, a number of NB cell lines may be termed resistant to RA as they fail to growth arrest and differentiate. In studying the mechanism mediating RA-resistance, we noted that invariably RA-resistant NB cell lines constitutively express Insulin-like Growth Factor 2 (IGF2) (Gaetano, 1991b). The NB cell line LAN-1-15N (15N) represented an interesting model in which to study the development of RA-resistance as initially 15N cells are growth arrested by RA, however with prolonged culture (8-10 days) cells begin to proliferate. Coincidentally, RA induces IGF2 mRNA and protein secretion in 15N NB cells (Matsumoto, 1992). In this study we isolated RA-resistant 15N cell lines and analyzed their growth properties and changes in cell cycle related (cdc2, cdk2, cyclins A, B, D and E) and early response (fos and jun) gene expression to evaluate the role IGF2 may play in mediating RA resistance. We found that exogenous IGF2 stimulates growth in 15N and is capable of altering RA induced inhibition of NB cell growth. Finally we show that by blocking the Insulin-like Growth Factor Receptor (IGF1_R) with a monoclonal antibody (α-IR3) in the presence of RA the growth of RAR cell lines could be completely blocked. These data are consistent with the concept that signals by IGF2 and transduced via the IGF1_R can mediate resistance to the growth inhibiting properties of RA.