title: 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.
abstract: 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 microM) 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.
authors.affiliation: Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Angela
authors.initials: A
authors.lastname: Kolberg
authors.forename: Tatiana Gomes
authors.initials: TG
authors.lastname: Rosa
authors.forename: Minéia Taíse
authors.initials: MT
authors.lastname: Puhl
authors.forename: Gustavo
authors.initials: G
authors.lastname: Scola
authors.forename: Daiane
authors.initials: D
authors.lastname: da Rocha Janner
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maslinkiewicz
authors.forename: Denise Jacques
authors.initials: DJ
authors.lastname: Lagranha
authors.forename: Thiago Gomes
authors.initials: TG
authors.lastname: Heck
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Paulo Ivo Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D000818:Animals; D002279:Carcinoma 256, Walker / Q000378:metabolism*; D002470:Cell Survival; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000378:metabolism; D007700:Kinetics; D008198:Lymph Nodes; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D005810:Multigene Family; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*; D009929:Organ Size; D011454:Prostaglandins A / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013950:Thymus Gland
chemical_list: D003517:Cyclopentanes; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide; D005982:Glutathione Transferase; D018840:HSP70 Heat-Shock Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011454:Prostaglandins A; C086860:glutathione transporter; C100008:prostaglandin A2; C013905:cyclopentenone; C421109:multidrug resistance-associated protein 1