Evidence for control of nitric oxide synthesis by intracellular transforming growth factor-β1 in tumor cells -: Implications for tumor development
Evidence for control of nitric oxide synthesis by intracellular transforming growth factor-β1 in tumor cells -: Implications for tumor development
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DOI：
10.1016/s0002-9440(10)65444-2
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发表时间：
1999-06-01
影响因子：
6
通讯作者：
Jeannin, JF
中科院分区：
文献类型：
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作者：
Lagadec, P;Raynal, S;Jeannin, JF
转化生长因子-β 1（TGF-β 1）已被证明在各种正常细胞中下调NO的合成。在本研究中，我们研究了TGF-β 1对肿瘤细胞中NO产生的影响及其对肿瘤发展的影响。在同基因BDM大鼠腹腔注射PROb结肠癌细胞的生长过程中，肿瘤内TGF-β 1浓度增加，而NO浓度保持非常低。腹腔注射脂质A诱导的肿瘤消退与TGF-β 1的减少和NO肿瘤内浓度的增加相关。在这些肿瘤中，PROb肿瘤细胞是NO和TGF-β 1分泌细胞。使用用编码TGF-β 1反义mRNA的表达载体转染的PROb细胞，我们在体外证明了TGF-β 1的分泌量与PROb细胞分泌NO的能力之间存在负相关性。由于在抗TGF-β II型受体中和抗体存在下获得了相同的结果，并且由于外源性TGF-β 1对PROb细胞的NO分泌没有任何影响，所以TGF-β 1通过细胞内机制明显下调PROb细胞中的NO合成。这些结果表明，内源性TGF-β 1构成了寻找新抗肿瘤药物的潜在靶点。
Transforming growth factor-beta 1 (TGF-beta 1) has been shown to down-regulate NO synthesis in a variety of normal cells. In the present study, we investigated the influence of TGF-beta 1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon carcinoma cells intraperitoneally injected in syngeneic BDM rats, intratumoral concentration of TGF-beta 1 increases while NO concentration stays very low. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-beta 1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-beta 1-secreting cells. Using PROb cells transfected with an expression vector coding for TGF-beta 1 antisense mRNA, we demonstrate in vitro that there is an inverse correlation between the amount of TGF-beta 1 secreted and the ability of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-beta type II receptor neutralizing antibody, and as exogenous TGF-beta 1 is without any effect on NO secretion by PROb cells, TGF-beta 1 apparently down-regulates NO synthesis in PROb cells by an intracellular mechanism. These results suggest that endogenous TGF-beta 1 constitutes a potential target in a search for new antitumoral agents.