Zinc adaptation and resistance to cadmium toxicity in mammalian cells. Molecular insight by proteomic analysis

TL;DR

This study uses proteomic analysis to uncover proteins and pathways involved in mammalian cell adaptation and resistance to cadmium toxicity, focusing on zinc-resistant human epithelial cells and their biochemical responses.

Contribution

It identifies specific proteins and pathways, including 4-hydroxyphenylpyruvate dioxygenase, linked to zinc adaptation and cadmium resistance in mammalian cells, providing molecular insights.

Findings

ZR cells overproduce 4-hydroxyphenylpyruvate dioxygenase

Inhibition of this enzyme reduces cadmium resistance in ZR cells

Proteasome activity is not enhanced in ZR cells

Abstract

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