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(Received for publication, October 23, 1996, and in revised form, January 17, 1997)
From the Division of Hematology/Oncology, Department of Medicine,
Medical College of Wisconsin, Milwaukee, Wisconsin 53226
The mechanism of drug resistance to gallium
nitrate is not known. Since gallium can be incorporated into ferritin,
an iron storage protein that protects cells from iron toxicity, we
investigated whether ferritin expression was altered in
gallium-resistant (R) CCRF-CEM cells. We found that the ferritin
content of R cells was decreased, while heavy chain ferritin mRNA
levels and iron regulatory protein-1 (IRP-1) RNA binding activity were
increased. IRP-1 protein levels were similar in gallium-sensitive (S)
and R cells, indicating that R cells contain a greater proportion of
IRP-1 in a high affinity mRNA binding state. 59Fe
uptake and transferrin receptor expression were decreased in R cells.
In both S and R cells, gallium inhibited cellular 59Fe
uptake, increased ferritin mRNA and protein, and decreased IRP-1
binding activity. Gallium uptake by R cells was markedly diminished;
however, the sensitivity of R cells to gallium could be restored by
increasing their uptake of gallium with excess transferrin. Our results
suggest that R cells have developed resistance to gallium by
down-regulating their uptake of gallium. In parallel, iron uptake by R
cells is also decreased, leading to changes in iron homeostasis.
Furthermore, since gallium has divergent effects on iron uptake and
ferritin synthesis, its action may also include a direct effect on
ferritin mRNA induction and IRP-1 activity.
Volume 272, Number 18,
Issue of May 2, 1997
pp. 12151-12157
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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