TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells.
TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells.
复制标题
DOI：
10.1186/bcr2095
复制
发表时间：
2008
影响因子：
7.4
通讯作者：
Tari, Ana M.
中科院分区：
文献类型：
--
作者：
Simeone, Ann-Marie;McMurtry, Vanity;Nieves-Alicea, Rene;Saavedra, Joseph E.;Keefer, Larry K.;Johnson, Marcella M.;Tari, Ana M.
肿瘤的侵袭和转移仍然是乳腺癌患者死亡的主要原因。体内高浓度的一氧化氮(NO)抑制肿瘤的侵袭和转移。NO前体药物通过适当的细胞内酶代谢产生大量的NO，因此有可能在乳腺癌的预防和治疗中发挥作用。本研究旨在探讨NO释放前体药物O2-(2，4-二硝基苯基)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1，2-diolate(JS-K)对乳腺癌侵袭的影响及其机制。MDA-MB-231、MDA-MB-231/F10和MCF-7/COX-2为三种乳腺癌细胞株。用NO试剂盒分光光度法测定NO水平。用Matrigel侵袭试验、基质金属蛋白酶阵列试剂盒和ELISAs检测细胞侵袭能力和基质金属蛋白酶及其组织抑制因子的表达。免疫印迹法检测细胞外信号调节激酶1/2、p38和c-jun氨基末端有丝分裂原活化蛋白激酶的活性和表达。在JS-K无细胞毒性的条件下，JS-K可显著降低乳腺癌细胞跨Matrigel基底膜的侵袭力(P<；0.05)，这与NO的产生直接相关。JS-43-126是JS-K的非释放类似物，对NO水平和侵袭力均无影响。JS-K增加(P<；0.05)TIMP-2的产生，用中和抗体阻断TIMP-2的活性显著增加(P<；0.05)JS-K处理的细胞对Matrigel的侵袭活性。JS-K降低p38活性，但不影响细胞外信号调节激酶1/2和c-jun氨基末端激酶的活性和表达。我们报道了新的发现，JS-K抑制乳腺癌跨Matrigel基底膜的侵袭，而NO的产生对这一活动是至关重要的。上调TIMP-2的产生是JS-K介导其抗侵袭作用的机制之一。JS-K和其他NO前体药物可能代表着预防和治疗转移性乳腺癌的一种创新的生物学方法。
Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. High concentrations of nitric oxide (NO) suppress tumor invasion and metastasis in vivo. NO prodrugs generate large amounts of NO upon metabolism by appropriate intracellular enzymes, and therefore could have potential in the prevention and therapy of metastatic breast cancer. The present study was designed to determine the effects of the NO-releasing prodrug O2-(2,4-dinitrophenyl) 1- [(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) on breast cancer invasion and the mechanisms involved. MDA-MB-231, MDA-MB-231/F10, and MCF-7/COX-2 were the three breast cancer cell lines tested. NO levels were determined spectrophotometrically using a NO assay kit. Invasion and the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs were determined using Matrigel invasion assays, an MMP array kit and ELISAs. The activity and expression of extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases were determined using western blot analyses. Under conditions by which JS-K was not cytotoxic, JS-K significantly decreased (P < 0.05) the invasiveness of breast cancer cells across the Matrigel basement membrane, which was directly correlated with NO production. JS-43-126, a non-NO-releasing analog of JS-K, had no effect on NO levels or invasion. JS-K increased (P < 0.05) TIMP-2 production, and blocking TIMP-2 activity with a neutralizing antibody significantly increased (P < 0.05) the invasive activity of JS-K-treated cells across Matrigel. JS-K decreased p38 activity, whereas the activity and the expression of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase were unaffected. We report the novel findings that JS-K inhibits breast cancer invasion across the Matrigel basement membrane, and NO production is vital for this activity. Upregulation of TIMP-2 production is one mechanism by which JS-K mediates its anti-invasive effects. JS-K and other NO prodrugs may represent an innovative biological approach in the prevention and treatment of metastatic breast cancer.
登录
查看更多内容
影响因子：
8.8
作者：
Howie, A F;Miller, W R;Hawkins, R A;Hutchinson, A R;Beckett, G J
通讯作者：
Beckett, G J
影响因子：
6.2
作者：
Denkert, C;Winzer, KJ;Hauptmann, S
通讯作者：
Hauptmann, S
影响因子：
4.1
作者：
Park, MJ;Park, IC;Lee, SH
通讯作者：
Lee, SH
影响因子：
11.2
作者：
Hall, Christopher L.;Dai, JinLu;Long, Michael W.
通讯作者：
Long, Michael W.
影响因子：
6.1
作者：
Hirai, Y;Migita, K;Eguchi, K
通讯作者：
Eguchi, K