All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-κB, activated protein-1 and apoptosis in human lung cancer cells
All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-κB, activated protein-1 and apoptosis in human lung cancer cells
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DOI：
10.1038/sj.onc.1203547
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发表时间：
2000-04-20
期刊：
影响因子：
8
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
--
作者：
Manna, SK;Aggarwal, BB
类维生素A调节TNF的生长和分化作用，但其机制尚不清楚。在这项研究中，我们研究了全反式维甲酸（ATRA）对各种人肺癌细胞系的细胞表面TNF受体表达和受体介导的信号转导的影响。ATRA处理表达野生型p53（A549和H460），或空p53（H1299），或突变型p53（H596）的细胞增加TNF受体的数量，如通过I-125标记的TNF与这些细胞的特异性结合所确定的，以剂量和时间依赖性方式。在37 ℃下用2 μ M ATRA处理24小时产生最大增加。Scatchard分析表明，ATRA诱导的增加是由于受体数量的增加，而不是亲和力的增加。TNF受体的上调也被共价受体-配体交联研究证实。TNF受体的增加使H596细胞对TNF诱导的NF-κ B、AP-1的活化和凋亡敏感，而A549细胞对TNF诱导的NF-κ B、AP-1的活化和凋亡完全抵抗。总之，我们的研究结果表明，ATRA诱导人肺癌细胞中的TNF受体，这使它们对TNF诱导的信号转导敏感，导致NF-κ B，AP-1和凋亡的活化。
Retinoids modulate the growth and differentiation effects of TNF but the mechanism is not understood. In this study, we investigated the effect of all-tr all-trans-retinoic acid (ATRA) on the cell surface expression of TNF receptors and receptor-mediated signaling in various human lung cancer cell lines. ATRA treatment of cells that express wild-type p53 (A549 and H460), or null p53 (H1299), or mutant p53 (H596) increased the number of TNF receptors, as determined by the specific binding of I-125-labeled TNF to these cells, in a dose- and time-dependent manner. Treatment with 2 mu M ATRA for 24 h at 37 degrees C produced the maximal increase. Scatchard analysis indicated that the increase inducted by ATRA was due to an increase in receptor number and not to an increase in affinity. The upmodulation of TNF receptors nas also confirmed by covalent receptor-ligand cross-linking studies. The increase in TNF receptors sensitized H596 cells to TNF-induced activation of NF-kappa B, AP-1 and apoptosis, A549 cells, however, were completely resistant to TNF-induced activation of NF-kappa B, AP-1 and apoptosis, Treatment of these cells with as little as 0.5 mu M ATRA was effective in converting TNF-resistant cells to TNF-sensitive. Overall our results indicate that ATRA induces the TNF receptors in human lung cancer cells, which sensitizes them to TNF-induced signaling leading to activation of NF-kappa B, AP-1 and apoptosis.