NUCLEOPHILIC DISTRIBUTION OF METALLOTHIONEIN IN HUMAN TUMOR-CELLS

Metallothionein (MT), a major zinc-binding intracellular protein thiol , has been associated with cytoprotection from heavy metals, antineopl astic drugs, mutagens, and cellular oxidants. Despite its small mass ( 7 kDa), nuclear partitioning of MT has been observed in both normal an d malignant tissues. The factors controlling MT sequestration are unkn own. Thus, we examined the regulation of MT subcellular distribution i n human cancer cell lines that exhibit prominent nuclear MT. The nucle ar disposition of MT was unaltered during cell cycle passage in synchr onized cells. MT redistributed to the cytoplasm when cells were expose d to reduced temperature. Cytoplasmic redistribution was also seen in DU-145 and HPC36M prostatic cancer cells after ATP depletion, but not in PC3-MA2 and SCC25/CP cells. Pretreatment with 10 mu M CdCl2 did not significantly alter MT distribution but did render all cells sensitiv e to cytoplasmic redistribution after either reduced temperature or AT P depletion. Thus, nuclear retention of MT is energy requiring and thi s ability of MT to accumulate in subcellular compartments against its concentration gradient may be important in the capacity of MT to suppl y Zn or other metals to target sites within the cell. (C) 1996 Academi c Press, Inc.