TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES GROWTH-INHIBITION OF A HUMAN MEDULLARY-THYROID CARCINOMA CELL-LINE DESPITE AN INCREASE IN STEADY-STATE C-MYC MESSENGER-RIBONUCLEIC-ACID LEVELS

Medullary thyroid cancer (MTC) is an endocrine tumor of the thyroid C- cells which provides an important experimental model for studies of tu mor differentiation and progression. We investigated the effects of tr ansforming growth factor-beta 1 (TGF beta 1) on the growth and functio nal characteristics of a human medullary thyroid carcinoma cell line ( TT). Because the c-myc protooncogene may play an important role in the growth inhibition induced by TGF beta 1, we also assessed steady stat e c-myc messenger RNA (mRNA) levels in these cells. A 6-day exposure o f TT cells to TGF beta 1 resulted in a dose-dependent inhibition of ce ll proliferation. In addition, TGF beta 1 exposure led to a 3-fold inc rease in nonadherent floating TT cells in the culture supernatants. Th e floating cells exhibited ultrastructural features of dying or apopto tic cells, including chromatin condensation, cytoplasmic and nuclear v esicularization, and DNA degradation with evidence of internucleosomal state c-mye mRNA levels were 3.6 +/- 0.6-fold higher in cells exposed to TGF beta 1 compared to those in control cells (P < 0.001). Exposur e of cells to a 15-base antisense c-myc oligonucleotide (10 mu M) resu lted in an attenuation of the TGF beta 1-induced growth inhibition and induction of cell death. TGF beta 1 also resulted in an approximately 3-fold decrease in steady state calcitonin and calcitonin gene-relate d peptide mRNA levels. Finally, using a sensitive bioassay for TGF bet a, TT cells were shown to produce and activate significant amounts of TGF beta, particularly under conditions of serum deprivation. Our data thus indicate that TGF beta 1 has multiple effects on TT cell growth and function. It induces growth inhibition in the presence of an incre ase in steady state mRNA levels of the c-myc protooncogene, which is u sually associated with cell proliferation. In addition, TGF beta 1 acc elerates apoptosis in TT cells.