INHIBITION OF ZINC-INDUCED METALLOTHIONEIN MESSENGER-RNA ACCUMULATIONBY GONADOTROPIN-RELEASING-HORMONE IN HUMAN HEPATOCARCINOMA CELL-LINE HEPG2

Recently we have demonstrated that the human hepatocellular carcinoma- derived cell lines, HepG2 and HuH7, contain gonadotropin-releasing hor mone (gonadoliberin) receptors and respond to various molecular forms of gonadoliberin in terms of suppressed proliferation in vitro. This s tudy provides the first demonstration that gonadoliberin inhibits the zinc-induced production of metallothionein mRNA in HepG2 and HuH7 cell s. Administration of gonadoliberin agonist (gonadoliberin-A) inhibited the Zn-induced metallothionein mRNA level in a time-related and dose- related manner. The effect of gonadoliberin-A was found to be specific , because concomitant treatment with a gonadoliberin antagonist (gonad oliberin-ANT) blocked gonadoliberin-A inhibition of metallothionein mR NA accumulation. Furthermore, the gonadoliberin-A-induced inhibition o f Zn-mediated metallothionein accumulation was found to correlate clos ely with suppresion of sell proliferation and [H-3]thymidine uptake in these cells. It is known that the metal-binding protein metallothione in plays an important rule in tumor cell pathobiology and resistance t o chemotherapeutic drugs. The present findings may have important impl ications in the development of an effective chemotherapy for treatment of human liver cancer, in part, by improving the sensitivity of tumor cells through suppression of metallothionein production by gonadolibe rin peptides.