Osteopontin induces nuclear factor κB-mediated promatrix metalloproteinase-2 activation through IκBα/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways
Osteopontin induces nuclear factor κB-mediated promatrix metalloproteinase-2 activation through IκBα/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways
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DOI：
10.1074/jbc.m207309200
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发表时间：
2003-04-18
影响因子：
4.8
通讯作者：
Kundu, GC
中科院分区：
文献类型：
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作者：
Philip, S;Kundu, GC
我们最近报道了骨桥蛋白（OPN）通过核因子kappaB （NFkappaB）介导的膜型1基质金属蛋白酶（MT1-MMP）在小鼠黑色素瘤细胞中刺激肿瘤生长和前基质金属蛋白酶-2 （pro-MMP-2）的激活（Philip， S., bulbulle， A., and Kundu， G. C. (2001) J.生物化学，276,44926-44935）。然而，在小鼠黑色素瘤（B16F10）细胞中，OPN激活NFkappaB并调节pro-MMP-2活化的分子机制尚不清楚。我们还研究了姜黄素（异丙基甲烷）对opn诱导的nfkappab介导的B16F10细胞中前mmp -2活化的作用机制。在这里，我们报道了OPN通过诱导这些细胞中IkappaB激酶（IKK）的活性，诱导核因子kappaB抑制剂（IkappaBalpha）的磷酸化和降解。OPN还诱导NFkappaB p65的核积累、NFkappaB- dna结合和反激活。然而，姜黄素是一种已知的抗炎和抗癌药物，通过抑制IKK活性来抑制opn诱导的IkappaBalpha磷酸化和降解。此外，我们的数据显示姜黄素抑制opn诱导的p65易位、NFkappaB- dna结合和NFkappaB转录活性。姜黄素也显著降低了opn诱导的pro-MMP-2激活和MT1-MMP表达。姜黄素还能抑制OPN诱导的细胞增殖、细胞迁移、细胞外基质侵袭，并与OPN协同诱导这些细胞的凋亡形态。最重要的是，姜黄素抑制了opn诱导的裸鼠肿瘤生长，并且在opn诱导的肿瘤中，姜黄素抑制了pro-MMP-2的表达和激活水平。据我们所知，这是第一次报道OPN通过激活IKK磷酸化和降解lkappaBalpha来诱导NFkappaB活性，最终触发pro-MMP-2的激活，并进一步证明姜黄素通过阻断IKK/IkappaBalpha信号通路，有效抑制OPN诱导的细胞迁移、肿瘤生长和NFkappaB介导的pro-MMP-2激活。
We have recently reported that osteopontin (OPN) stimulates tumor growth and activation of promatrix metalloproteinase-2 (pro-MMP-2) through nuclear factor kappaB (NFkappaB)-mediated induction of membrane type 1 matrix metalloproteinase (MT1-MMP) in murine melanoma cells (Philip, S., Bulbule, A., and Kundu, G. C. (2001) J. BioL Chem. 276, 44926-44935). However, the molecular mechanism by which OPN activates NFkappaB and regulates pro-MMP-2 activation in murine melanoma (B16F10) cells is not well defined. We also investigated the mechanism of action of curcumin (diferulolylmethane) on OPN-induced NFkappaB-mediated activation of pro-MMP-2 in B16F10 cells. Here we report that OPN induces phosphorylation and degradation of the inhibitor of nuclear factor kappaB (IkappaBalpha) by inducing the activity of IkappaB kinase (IKK) in these cells. OPN also induces the nuclear accumulation of NFkappaB p65, NFkappaB-DNA binding, and transactivation. However, curcumin a known antiinflammatory and anticarcinogenic agent suppressed OPN-induced IkappaBalpha phosphorylation and degradation by inhibiting the IKK activity. Moreover, our data revealed that curcumin inhibited the OPN-induced translocation of p65, NFkappaB-DNA binding, and NFkappaB transcriptional activity. The OPN-induced pro-MMP-2 activation and MT1-MMP expression were also drastically reduced by curcumin. Curcumin also inhibited OPN-induced cell proliferation, cell migration, extracellular matrix invasion, and synergistically induced apoptotic morphology with OPN in these cells. Most importantly, curcumin suppressed the OPN-induced tumor growth in nude mice, and the levels of pro-MMP-2 expression and activation in OPN-induced tumor were inhibited by curcumin. To our knowledge, this is the first report that OPN induces NFkappaB activity through phosphorylation and degradation of lkappaBalpha by activating IKK that ultimately triggers the activation of pro-MMP-2 and further demonstrates that curcumin potently suppresses OPN-induced cell migration, tumor growth, and NFkappaB-mediated pro-MMP-2 activation by blocking the IKK/IkappaBalpha signaling pathways.