Glutathione metabolism and glutathione S-conjugate export ATPase (MRP1/GS-X pump) activity in cancer. II. Cell-to-cell variability, relation with cellular activation state and functional absence of GS-X pump in lymphocytes.
A severe complication in late-stage cancer patients is host immunosuppression. It is suggested that overproduction of the highly cytostatic and cytotoxic antiproliferative cyclopentenone prostaglandins (CP-PGs) within the plasma of cancer-bearing subjects may contribute to immunosuppression. Lymphoid tissues of Walker 256 tumor-bearing rats accumulate large amounts of CP-PGs while the tumor tissue itself does not. Moreover, tumor cells may present differential sensitivity to CP-PGs due to the expression of the multidrug resistance-associated protein (MRP1) gene product which shows a Mg(2+)-dependent vanadate-sensitive glutathione S-conjugate export ATPase (GS-X pump) activity that extrudes CP-PGs from cells as glutathione S-conjugates. In this study, the possibility that deficient GS-X pump activity in immune cells that may be involved in the accumulation of CP-PGs is investigated. Rat lymph node lymphocytes do not exhibit any notable activity even when mitogen-stimulated. Conversely, although rat peritoneal resident (quiescent) or thioglycollate-stimulated (inflammatory) macrophages exhibit low GS-X pump activity, Bacillus Calmette-Guérin (BCG)-activated macrophages show a notable rise in the activity of the ATPase, suggesting that the cellular activation state may modulate GS-X pump activity/expression and that, under appropriate stimuli (e.g., during immune response) macrophages may provide a self-defense against electrophilic CP-PGs by forming GS-conjugates that can be extruded from cells through the GS-X pump. ras oncogene expression may be linked with MRP1/GS-X pump expression/activity, since C2C12 promyoblasts transformed by v-H-ras transfection doubled GS-X pump activity. These results support the proposition that the accumulation of CP-PGs and the immunosuppression of tumor-bearing subjects may be attributed to a lack of GS-X pump activity/expression in lymphocytes.
de Bittencourt Júnior
P I
PI
Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. pauloivo@vortex.ufrgs.br
Senna
S M
SM
Vidor
A C
AC
Miyasaka
C K
CK
Curi
R
R
Williams
J F
JF
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D014407:Tumor Cells, Cultured
D000251:Adenosine Triphosphatases; C068387:S-(dinitrophenyl)glutathione ATPase; D005978:Glutathione