Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells
Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells
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DOI：
10.1038/sj.leu.2400739
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发表时间：
1997-08-01
期刊：
影响因子：
11.4
通讯作者：
Buckley, AR
中科院分区：
文献类型：
--
作者：
Gout, PW;Kang, YJ;Buckley, AR
对表现出不同程度恶性进展的大鼠前T细胞“Nb 2淋巴瘤”亚系的分析可以指示可能用作治疗靶点的表型变化。在本研究中，比较了催乳素（细胞因子）依赖性Nb 2 -11和自主性Nb 2-SFJCD 1亚系的体外巯基生长要求。而Nb 2 -11培养生长依赖于2-巯基乙醇（2-ME; 33-100 μ M），Nb 2-SFJCD 1细胞是2-NE-独立的。这种差异源于外源性L-胱氨酸的差异吸收，增殖所必需的。摄取S-35-L-胱氨酸（μ Ci/ml; 40 μ M）显示Nb 2 -11细胞具有低胱氨酸摄取能力; 2-ME将胱氨酸摄取增强至生长维持水平。Nb 2-SFJCD 1细胞不需要2-ME，因为通过x（c）（-）胱氨酸/谷氨酸转运系统的内在的11倍高的胱氨酸摄取。在不存在2-ME的情况下，N-谷氨酸通过特异性抑制胱氨酸摄取（在10 mM下85%）来废除Nb 2-SFJCD 1增殖。升高的谷胱甘肽（GSH）水平对于任一品系的生长都不是必需的，如用L-丁硫氨酸-（S，R）-亚砜亚胺（0.1-4 mM）处理所示。因此，胱氨酸的需求主要不涉及维持正常的GSH水平，据报道，这对T淋巴细胞复制至关重要。这些和其他结果表明，增加的胱氨酸摄取能力构成T细胞癌进展中的另一个潜在步骤，其不与细胞因子自主性或转移能力发展偶联。x（c）（-）转运系统显然为T细胞癌症治疗提供了新的靶点。其抑制作用会抑制某些进展细胞的胱氨酸摄取，也会干扰胱氨酸摄取，以及随后的半胱氨酸释放，例如巨噬细胞，被认为在半胱氨酸递送至淋巴细胞中起作用。
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 mu M), Nb2-SFJCD1 cells were 2-NE-independent. This difference stemmed from differential uptake of exogenous L-cystine, critically required for proliferation. Uptake of S-35-L-cystine (in mu Ci/ml; 40 mu M) 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/gtutamate 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.