Role of determinants of cadmium sensitivity in the tolerance of Schizosaccharomyces pombe to cisplatin.
The genetic mechanisms underlying cisplatin (DDP) resistance in yeast were investigated by examining the cytotoxicity of DDP to Schizosaccharomyces pombe mutants that were either hypersensitive or resistant to Cd. Despite reports that have linked glutathione (GSH) to DDP resistance in human cancer cells, we found that a mutant of S. pombe that was hypersensitive to Cd by virtue of a 15-fold reduction in GSH level and lack of phytochelatin production was as tolerant as the wild-type strain to DDP. A mutant that harbored a mutation in hmt1, the gene encoding an ATP-binding cassette-type transporter for vacuolar sequestration of a phytochelatin/Cd complex, exhibited only mild hypersensitivity to DDP even though it was 100-fold more sensitive to Cd. Overexpression of hmt1 in wild-type or mutant cells conferred tolerance to Cd but failed to do the same for DDP. However, a strain that produced 6-fold more sulfide than wild-type cells was found to be 6-fold more resistant to DDP and twice as resistant to Cd; an association between DDP resistance and sulfide production was observed in three other strains that were examined, and overproduction of sulfide was accompanied by reduced platination of DNA. These results indicate that GSH and the GSH-derived phytochelatin peptides do not play critical roles in determining sensitivity to DDP in S. pombe but rather identify increased production of sulfide as a possible new mechanism of DDP resistance that may also be relevant to human cells.
Perego
P
P
Department of Medicine, University of California, San Diego, USA. perego@icil64.cilea.it
Vande Weghe
J
J
Ow
D W
DW
Howell
S B
SB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D005978:Glutathione / Q000502:physiology; D008667:Metalloproteins / Q000502:physiology; D054811:Phytochelatins; D010940:Plant Proteins / Q000502:physiology; D012568:Schizosaccharomyces / Q000187:drug effects*; D013440:Sulfides / Q000378:metabolism
D000970:Antineoplastic Agents; D008667:Metalloproteins; D010940:Plant Proteins; D013440:Sulfides; D002104:Cadmium; D054811:Phytochelatins; D005978:Glutathione; D002945:Cisplatin