Premium
Low expression of MRP1 /GS‐X pump ATPase in lymphocytes of Walker 256 tumour‐bearing rats is associated with cyclopentenone prostaglandin accumulation and cancer immunodeficiency
Author(s) -
Kolberg Angela,
Rosa Tatiana Gomes,
Puhl Minéia Taíse,
Scola Gustavo,
Janner Daiane da Rocha,
Maslinkiewicz Alexandre,
Lagranha Denise Jacques,
Heck Thiago Gomes,
Curi Rui,
de Bittencourt Paulo Ivo Homem
Publication year - 2005
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.1290
Subject(s) - glutathione , lymphocyte , biology , heat shock protein , extracellular , immune system , transfection , microbiology and biotechnology , biochemistry , endocrinology , immunology , gene , enzyme
Immunosuppression is a life‐threatening complication of late cancer stages. In this regard, overproduction in the host plasma of the anti‐inflammatory cyclopentenone prostaglandins (CP‐PGs), which are strongly antiproliferative at high concentrations, may impair immune function. In fact, lymphoid tissues of tumour‐bearing rats accumulated large amounts of CP‐PGs while the tumour tissue itself did not. Expression of the CP‐PG‐induced 72‐kDa heat shock protein (hsp70) was elevated in lymphocytes from tumour‐bearing animals related to controls. As the capacity for CP‐PG uptake by lymphocytes is the same as tumour cells, we investigated whether the latter could overexpress the multidrug resistance‐associated protein ( MRP1 /GS‐X pump) which extrudes CP‐PGs towards the extracellular space as glutathione S ‐conjugates. Walker 256 tumour cells extruded 15‐fold more S‐conjugates than lymphocytes from the same rats ( p < 0.001). This did not appear to be related to deficiency in lymphocyte glutathione (GSH) metabolism, since the major GSH metabolic routes are consistent with CP‐PG conjugation in lymphocytes. This was not the case, however, for the MRP1 /GS‐X pump activity in lymphocyte membranes (in pmol/min/mg protein: 3.1 ± 1.7 from normal rats, 0.2 ± 0.2 from tumour‐bearing animals vs 64.3 ± 7.0 in tumour cells) which was confirmed by Western blot analysis for MRP1 protein. Transfection of lymphocytes with MRP1 gene completely abolished CP‐PG (0–40 μM) toxicity. Taken together, these findings suggest that CP‐PG accumulation in lymphocytes may be, at least partially, responsible for cancer immunodeficiency. Clinical approaches for overexpressing MRP1 /GS‐X pump in lymphocytes could then play a role as a tool for the management of cancer therapeutics. Copyright © 2005 John Wiley & Sons, Ltd.