Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells.
Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells.
复制标题
通过转化生长因子-β1 和表皮生长因子协同诱导环氧合酶-2，抑制上皮细胞凋亡。
DOI：
10.1038/sj.neo.7900051
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Beauchamp,RD
中科院分区：
文献类型：
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作者：
Saha,D;Datta,PK;Sheng,H;Morrow,JD;Wada,M;Moses,HL;Beauchamp,RD
环氧合酶-2(COX-2)在几种人类肿瘤类型以及特定的动物和细胞致癌模型(包括肺癌)中的表达增加。COX-2的表达增加和前列腺素的产生可能通过抑制细胞凋亡、增加与细胞外基质的黏附、增加侵袭力、刺激血管生成而为转化细胞提供生存优势。在本研究中，我们发现转化生长因子β-1和表皮生长因子协同诱导水貂肺上皮细胞环氧合酶-2的表达和前列腺素E_2的产生。表皮生长因子能抑制转化生长因子-β1诱导的MVILu细胞的凋亡，而PDGF或IGF-1则不能。这一作用可被COX-2活性的选择性抑制剂NS-398阻断，提示COX-2可能在表皮生长因子受体配体的抗凋亡作用中起作用。联合应用转化生长因子-β-1和表皮生长因子也可显著诱导大鼠肠上皮细胞COX-2的表达，并完全阻断丁酸钠诱导的细胞凋亡。在缺乏转化生长因子-β-I受体的MVI Lu细胞系R1b-L17细胞中，未观察到转化生长因子-β1和表皮生长因子对COX-2的协同诱导作用。表皮生长因子受体酪氨酸激酶活性的选择性抑制剂AG1478可完全抑制表皮生长因子或转化生长因子-β1+表皮生长因子诱导的COX-2表达。P38MAPK的特异性抑制剂SB203580和p38MAPK的特异性抑制剂PD98059可显著抑制表皮生长因子和转化生长因子-β-1联合诱导的COX-2的产生。这些结果提示，β-1和表皮生长因子信号在诱导Mv1Lu细胞COX-2和前列腺素的产生中起着重要的协同作用。
Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, the stimulation of angiogenesis. In the present studies, we found that transforming growth factor β1 (TGF-β1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2(PGE2) production in mink lung epithelial (Mvi Lu) cells. EGF, but not PDGF orIGF-1, was able to inhibit TGF-β1-induced apoptosis in Mvi Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptosic effect of EGF receptor ligands. The combination of TGF-β1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-β1 and EGF was not observed in R1B-L17 cells, a line derived from Mvi Lu cells that lacks the TGF-β type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-β1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-β1. These results suggest an important collaborative interaction of TGF-β1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.