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Rottlerin stimulates metallothionein gene expression but inhibits metal transport in Chinese hamster ovary cells.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2001 Dec 15; Vol. 177 (3), pp. 256-63. - Publication Year :
- 2001
-
Abstract
- Metallothionein (MT) can be induced by various metals. We have shown previously that H7, a protein kinase C (PKC) inhibitor, inactivates metal-induced MT gene expression. To investigate whether a specific PKC isoform is involved in the induction process, inhibitors for various PKC isoforms were administered to cadmium-resistant Chinese hamster ovary (Cd(R)) cells. None of the inhibitors used can reduce metal-induced MT gene expression. However, a PKCdelta inhibitor, rottlerin, induced MT mRNA expression in Cd(R) cells in the presence or absence of Cd. Notably, the induction occurs through the activation of the MT transcriptional factor (MTF-1) and is not related to an increase of metal influx. Furthermore, metal accumulation is reduced in the presence of rottlerin. Pulse-labeling analysis indicated that MT protein synthesis increased in Cd(R) cells upon rottlerin treatment. These results suggest that rottlerin blocks metal transport but stimulates MT synthesis in Cd(R) cells. Since rottlerin is capable of reducing the cellular accumulation of Cd, it was expected that the cytotoxic effect of Cd would decrease in the presence of rottlerin. Treating the parental cell of Cd(R) with Cd and rottlerin together indeed showed a decline of cytotoxicity compared to cells treated with Cd alone. We further examined how MTF-1 was activated by rottlerin. Rottlerin-induced MTF-1 activity was not affected in Cd(R) cells by the addition of EDTA. It was, however, diminished by administering an intracellular Zn chelator, TPEN. The result implies a mobilization of intracellular Zn ions after rottlerin treatment in Cd(R) cells. To investigate whether the described results occur in all types of cells, another cell line (GH(3)) was used to study the effect of rottlerin on MT gene expression. The result revealed that rottlerin did not increase the amount of MT mRNA in GH(3) cells. This differential effect between cell lines may be useful for investigating the regulatory mechanism of MT gene expression.<br /> (c)2001 Elsevier Science.)
- Subjects :
- Animals
CHO Cells metabolism
Cadmium metabolism
Cell Survival drug effects
Chelating Agents pharmacology
Cricetinae
Dose-Response Relationship, Drug
Drug Resistance
Enzyme Induction drug effects
Enzyme Inhibitors pharmacology
Isoenzymes antagonists & inhibitors
Metallothionein genetics
Protein Kinase C antagonists & inhibitors
Protein Kinase C-delta
RNA, Messenger metabolism
Zinc metabolism
Acetophenones pharmacology
Benzopyrans pharmacology
CHO Cells drug effects
Gene Expression drug effects
Ion Transport drug effects
Metallothionein metabolism
Metals metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0041-008X
- Volume :
- 177
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11749125
- Full Text :
- https://doi.org/10.1006/taap.2001.9299