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Metallothionein Localization and Cisplatin Resistance in Human Hormone-independent Prostatic Tumor Cell Lines¹

Departments of Pharmacology [Y. K., S. M. K., J. S. L.] and Cell Biology and Physiology [S. C. W.], School of Medicine, and Experimental Therapeutics Program, Pittsburgh Cancer Institute [J. S. L., S. C. W.], University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Metallothioneins (MT) are major cysteine-rich proteins with poorly characterized functions. We have examined the MT amount, isotype expression, and subcellular distribution in 4 human hormone-independent prostatic carcinoma cell lines. Both PC-3 and DU-145 cells were thiol-rich cells with similar MT and glutathione levels, while HPC36M and PC-3 MA2 were thiol-poor cells with lower MT and glutathione levels. All 4 prostatic cell lines expressed the MTIIA isoform at a basal level; DU-145 cells also constitutively expressed MTIE mRNA. Using antibodies for both total MT and MTIIA, we defined MT to cytoplasmic and nuclear domains in PC-3 cells, to perinuclear and nuclear domains in HPC36M cells, and to prominent nonnucleolar nuclear domains in DU-145 and PC-3 MA2 cells. These results indicate that the subcellular distribution is cell type specific and not reflective of the total MT content or MT isoform. Resistance to cadmium in all 4 cell lines was correlated with total MT levels, while resistance to the anticancer agent cisplatin correlated best with nuclear MT content. We suggest that the subcellular localization of MT is functionally important in cellular protection against the anticancer agent cisplatin in human prostatic cancer cells.

¹ Supported in part by NIH Grant CA61299.

² Present address: Nutrition Program, 301 Parker Hall, State University of New York, Buffalo, NY 14214.

³ To whom requests for reprints should be addressed, at Department of Pharmacology, University of Pittsburgh, E1340 Biomedical Sciences, Towers, Pittsburgh, PA 15261.

Received 10/10/94. Accepted 12/19/94.