INDUCTION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND ITS RECEPTORS DURING ALL-TRANS-RETINOIC ACID (RA) TREATMENT OF RA-RESPONSIVE HUMAN NEUROBLASTOMA CELL-LINES

Recent work on a variety of normal and malignant cell lines has shown that induction and secretion of biologically active TGF-beta may occur after exposure to all-trans-retinoic acid (RA), coincident with decre ased growth rate and/or differentiation. This study evaluates the expr ession and regulation of transforming growth factor beta (TGF-beta) an d its receptors during RA-induced cell growth arrest and induction of differentiation in the RA-sensitive human neuroblastoma cell line SMS- KCNR and the RA-resistant neuroblastoma cell line SK-N-AS. RA treatmen t of SMS-KCNR cells results in a 40-fold increase in TGF-beta 1 mRNA a fter 4 days of RA, a dose-dependent increase in TGF-beta 1 secretion, an increase in types I (TBR(I)) and III (TBR(III)) TGF-beta receptor p roteins, and an increase in type II TGF-beta receptor (TBR(II)) mRNA c oincident with RA-responsiveness of the cells. However, in the RA-resi stant line SK-N-AS, TGF-beta 1 is constitutively secreted at levels th at are unchanged after RA treatment, and although TBR(I) and TBR(III) mRNA is expressed in untreated SK-N-AS cells, levels of TBR(I) and TBR (III) protein and TBR(II) mRNA decrease after RA treatment. Thus, in R A-sensitive neuroblastoma cells, RA treatment may result in the induct ion of a negative autocrine TGF-beta 1 growth regulatory loop. These r esults suggest the hypothesis that: (a) induction of a TGF-beta 1 nega tive autocrine growth loop may be a necessary component for RA-respons iveness of neuroblastoma cells in vivo; and (b) the inability to induc e or maintain this TGF-beta 1 negative autocrine growth loop may be a mechanism of RA resistance in neuroblastoma.