Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells.
Analysis of rat, pre-T cell 'Nb2 lymphoma' sublines, manifesting different degrees of malignant progression, can indicate phenotypic changes potentially useful as therapeutic targets. In this study, the prolactin (cytokine)-dependent Nb2-11 and autonomous Nb2-SFJCD1 sublines were compared for in vitro thiol growth requirements. Whereas Nb2-11 culture growth depended on 2-mercaptoethanol (2-ME; 33-100 microM), Nb2-SFJCD1 cells were 2-ME-independent. This difference stemmed from differential uptake of exogenous L-cystine, critically required for proliferation. Uptake of 35S-L-cystine (10 microCi/ml; 40 microM) showed Nb2-11 cells had low cystine uptake capability; 2-ME enhanced cystine uptake to growth-sustaining levels. Nb2-SFJCD1 cells did not require 2-ME due to intrinsic, 11-fold higher cystine uptake via the x(c)- cystine/glutamate transport system. In absence of 2-ME, monosodium glutamate abrogated Nb2-SFJCD1 proliferation by specifically inhibiting cystine uptake (85% at 10 mM). Elevated glutathione (GSH) levels were not essential for growth of either line as shown with L-buthionine-(S,R)-sulfoximine (0.1-4 mM) treatment. The cyst(e)ine requirement therefore did not primarily involve maintenance of normal GSH levels, reported critical for T lymphocyte replication. These and other results suggest increased cystine uptake capability constitutes another potential step in progression of T cell cancers which is not coupled to cytokine autonomy or metastatic ability development. The x(c)- transport system apparently provides a novel target for T cell cancer therapy. Its inhibition would suppress cystine uptake by certain progressed cells, and also interfere with cystine uptake, and subsequent cysteine release, by eg macrophages, thought to have a role in cysteine delivery to lymphoid cells.
Gout
P W
PW
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, Canada.
Kang
Y J
YJ
Buckley
D J
DJ
Bruchovsky
N
N
Buckley
A R
AR
D000818:Animals; D001692:Biological Transport; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003553:Cystine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005971:Glutamates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology*; D008623:Mercaptoethanol / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005971:Glutamates; D003553:Cystine; D019328:Buthionine Sulfoximine; D008623:Mercaptoethanol; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione