Document Detail

GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation.
MedLine Citation:
PMID:  7961875     Owner:  NLM     Status:  MEDLINE    
The ATP-dependent glutathione S-conjugate export pump, named GS-X pump, has been shown to eliminate a potentially cytotoxic glutathione-platinum (GS.Pt) complex from tumor cells, thereby modulating glutathione (GSH)-associated resistance to cis-diamminedichloroplatinum(II) (cisplatin) (Ishikawa, T., and Ali-Osman, F. (1993) J. Biol. Chem. 268, 20116-20125). The present study provides evidence that the GS-X pump is functionally overexpressed in cisplatin-resistant human promyelocytic leukemia HL-60 (HL-60/R-CP) cells, in which the cellular GSH level was substantially enhanced. Indeed, the rate of ATP-dependent transport of the GS.Pt complex, measured with plasma membrane vesicles, was about 4-fold greater in HL-60/R-CP cells than in HL-60 cells. Three membrane proteins with apparent molecular masses of 200, 110, and 70 kDa were overexpressed in HL-60/R-CP cells, whereas P-glycoprotein (MDR1) was not immunologically detected in the membrane preparations from resistant and sensitive cells. Unlike in HL-60 cells, increased numbers of intracellular vesicles were observed in the cytoplasm of HL-60/R-CP cells. Fluorescence microscopy with syn-(CICH2,CH3)-1,5-diazabicyclo-[3.3.0]-octa-3,6-dione-2,8-dione (monochlorobimane) revealed that the fluorescent glutathione S-conjugate accumulated in intracellular vesicles of the cisplatin-resistant cells in an energy-dependent manner. The GS-X pump is suggested to contribute to vesicle-mediated excretion of GSH-drug conjugates from cells. In addition, both HL-60 and HL-60/R-CP cells underwent cell differentiation in response to 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, and dimethyl sulfoxide, resulting in proliferation arrest as well as a remarkable decrease in the c-myc mRNA levels. After cell differentiation, a significant decrease was observed in the activity of ATP-dependent transport of the GS.Pt complex in membrane vesicles prepared from both HL-60/R-CP and HL-60 cells. These results suggest that the expression of the GS-X pump in both cisplatin-resistant and -sensitive cells is related to cell proliferation.
T Ishikawa; C D Wright; H Ishizuka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  269     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1994 Nov 
Date Detail:
Created Date:  1994-12-19     Completed Date:  1994-12-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  29085-93     Citation Subset:  IM    
Department of Experimental Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
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MeSH Terms
Adenosine Triphosphate / metabolism
Biological Transport
Carrier Proteins / metabolism*
Cell Differentiation
Cisplatin / pharmacology*
Dimethyl Sulfoxide / pharmacology
Drug Resistance
Glutathione / metabolism*
Leukemia / metabolism*
Membrane Proteins / metabolism
Membrane Transport Proteins
Tetradecanoylphorbol Acetate / pharmacology
Tretinoin / pharmacology
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Carrier Proteins; 0/Membrane Proteins; 0/Membrane Transport Proteins; 0/glutathione transporter; 15663-27-1/Cisplatin; 16561-29-8/Tetradecanoylphorbol Acetate; 302-79-4/Tretinoin; 56-65-5/Adenosine Triphosphate; 67-68-5/Dimethyl Sulfoxide; 70-18-8/Glutathione

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