Diversity of metallothionein content and subcellular localization in the National Cancer Institute tumor panel

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Abstract
Metallothioneins (MTs) are major thiol-containing intracellular proteins that bind metals, are induced by stress, and have been implicated in resistance to drugs and heavy metals. Purpose: To examine the hypothesis that the protective functionality of MT may be dictated by its subcellular localization. Methods: We analyzed the basal MT content in 53 adherent cell lines of the National Cancer Institute (NCI) tumor panel and quantified the nuclear/cytoplasmic distribution of MT using confocal laser scanning microscopy and a recently described immunofluorescence-based algorithm. Results: Among these cell types we found a 400-fold range in the basal MT levels and a tenfold range in the ratio of the nuclear to cytoplasmic MT immunostaining that was independent of basal MT content. Total MT levels and nuclear/cytoplasmic distribution were independent of total glutathione content, suggesting autonomous regulation of these protective protein and nonprotein thiol pools. Approximately 50% (29/53) of the cell lines had a greater nuclear than cytoplasmic MT density and were defined as having a karyophilic phenotype. Tissue specificity of MT localization was seen with breast cancer cell lines, which were cytoplasmophilic, whereas prostate-derived cells were karyophilic. Among the 25 000 unrestricted compounds in the NCI database, we detected a correlation between total basal MT levels and resistance to CdCl2, four Pt- and two Cu-containing compounds. High nuclear/cytoplasmic MT values correlated with resistance to six Cu-, six Pb-, and one Zn-containing compounds. Conclusions: These results demonstrated significant diversity in MT content and subcellular localization in human tumor cells. Moreover, both basal MT levels and subcellular distribution appeared to be determinants of cellular responsiveness to metal-containing compounds.

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