Zinc pyrithione induces apoptosis and increases expression of Bim.
We demonstrate herein that zinc pyrithione can induce apoptosis at nanomolar concentrations. Zinc pyrithione was a potent inducer of cell death causing greater than 40-60% apoptosis among murine thymocytes, murine splenic lymphocytes and human Ramos B and human Jurkat T cells. Conversely, the addition of a zinc chelator protected thymocytes against zinc pyrithione induced apoptosis indicating these responses were specific for zinc. Zinc-induced apoptosis was dependent on transcription and translation which suggested possible regulation by a proapoptotic protein. Indeed, zinc induced a 1.9 and 3.4 fold increase respectively in expression of the BimEL and BimL isoforms and also stimulated production of the most potent isoform, BimS. This increase in Bim isoform expression was dependent on transcription being blocked by treatment with actinomycin D. Overexpression of Bcl-2 or Bcl-xL provided substantial protection of Ramos B and Jurkat T cells against zinc-induced apoptosis. Zinc also activated the caspase cascade demonstrated by cleavage of caspase 9. Addition of specific inhibitors for caspase 9 and caspase 3 also blocked zinc-induced apoptosis. The data herein adds to the growing evidence that free or unbound zinc could be harmful to cells of the immune system.
Mann
J J
JJ
Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
Fraker
P J
PJ
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D011725:Pyridines / Q000494:pharmacology; D013054:Spectrophotometry, Atomic; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D009942:Organometallic Compounds; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D015032:Zinc; C010423:pyrithione zinc