GENES RELATED TO GROWTH AND INVASIVENESS ARE REPRESSED BY SODIUM-BUTYRATE IN OVARIAN-CARCINOMA CELLS

Down-regulation of oncogene expression is one of the hallmarks of the process whereby transformed cells are forced into differentiation and/ or growth arrest by potent inducers and therefore can represent an int erim end point in cancer treatment. The differentiation inducer sodium butyrate (NaB) arrested growth of N.1 ovarian carcinoma cells and rep ressed expression of cyclin D1/prad1 and the invasiveness-related prot ease plasminogen activator-urokinase (plau). This was accompanied by t he acquisition of a differentiated morphology, all of which characteri stics were maintained as long as N.1 cells were exposed to the inducer . In accordance with a differentiated phenotype was the finding that f ibronectin expression was increased significantly. Recently, it was sh own that NaB represses the transcription factor c-myc by blocking Ca2 signals and modulating serine threonine kinase activity. We wanted to investigate NaB-mediated interference on signals contributing to the expression of prad1, plau and growth arrest-specific 6 (gas6). Protein kinase A (PKA) inactivation de-repressed prad1 and plau transcript le vels. NaB had only general but no specific influence on PKA-modulated prad1 and plau expression however. Protein kinase C activation up-regu lated plau transcript levels, but not that of prad1. Prad1 expression seemed to depend on Ca2+-triggered signals. Constitutive plau expressi on was insensitive to additional Ga2+-mediated signals, but it became responsive upon NaB treatment.