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Department of Medicine and Cancer Center (P.P., S.B.H.), University
of California, San Diego, La Jolla, California 92093, and
Plant Gene
Expression Center, United States Department of Agriculture-Agriculture
Research Service/University of California, Berkeley, California
94720 (J.V.W., D.W.O).
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.
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