Abstract
Synthetic 4, 5-didehydro GGA (geranylgeranoic acid), a potent ligand both for cellular retinoic acid-binding protien and for nuclear retinoid receptors, induced apoptosis in human hepatoma-derived cell line HuH-7 but not in primary hepatocytes, although all-transor 9-cisretinoic acid did not induce any growth inhibition. Either exogenous transforming growth factor-α (TGFα) or epidermal growth factor (EGF) prevented the cells from apoptosis in the presence of 4, 5-didehydro GGA, but hepatocyte growth factor, insulin-like growth factor-II, insulin or triiodothyronine was essentially inactive. 4, 5-Didehydro GGA down-regulated the cellular levels of antibody induced apoptosis in HuH-7 cells without using the acid. Taken together, the present study strongly suggests that 4, 5-didehydro GGA induced apoptosis in HuH-7 cells through the destruction of autocrine loop consisting of TGFα and EGF receptor, due to the down-regulation of TGFα gene expression.
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