  To identify proteins involved in cellular adaptive responses to zinc, a
comparative proteome analysis between a previously developed high zinc- and
cadmium- resistant human epithelial cell line (HZR) and the parental HeLa cells
has been carried out. Differentially produced proteins included co-chaperones,
proteins associated with oxido-reductase activities, and ubiquitin. Biochemical
pathways to which these proteins belong were probed for their involvement in
the resistance of both cell lines against cadmium toxicity. Among endoplasmic
reticulum stressors, thapsigargin sensitized HZR cells, but not HeLa cells, to
cadmium toxicity more acutely than tunicamycin, implying that these cells
heavily relied on proper intracellular calcium distribution. The similar
sensitivity of both HeLa and HZR cells to inhibitors of the proteasome, such as
MG-132 or lactacystin, excluded improved proteasome activity as a mechanism
associated with zinc adaptation of HZR cells. The enzyme
4-hydroxyphenylpyruvate dioxygenase was overproduced in HZR cells as compared
to HeLa cells. It transforms 4-hydroxyphenylpyruvate to homogentisate in the
second step of tyrosine catabolism. Inhibition of 4-hydroxyphenylpyruvate
dioxygenase decreased the resistance of HZR cells against cadmium, but not that
of HeLa cells, suggesting that adaptation to zinc overload and increased
4-hydroxyphenylpyruvate removal are linked in HZR cells
