Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells
Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells
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DOI：
10.1073/pnas.94.2.657
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发表时间：
1997-01-21
影响因子：
11.1
通讯作者：
Morrow, JD
中科院分区：
文献类型：
--
作者：
Coffey, RJ;Hawkey, CJ;Morrow, JD
非甾体抗炎药降低结肠癌的风险，可能是通过抑制环氧合酶(COX)，生长因子诱导的COX-2，在肿瘤结肠组织中过表达，是一个有吸引力的靶点来介导这一作用。在这里，我们利用人结肠癌细胞系Hca-7 Colony 29在Transwell(Costar)过滤器上培养时极化的能力来研究COX-2的产生和前列腺素(PG)的载体释放，将A型转化生长因子注射到表皮生长因子受体(EGFR)所在的基底外侧室，结果细胞基底部COX-2免疫反应明显诱导，胞核意外出现COX-2。COX-2蛋白的增加与基底侧而不是顶端PG水平的剂量和时间依赖性增加有关，AmphiRegin是这些细胞中表达最丰富的EGFR配体，该蛋白存在于基底侧表面，EGFR阻断以浓度依赖的方式降低基线COX-2免疫反应性、PG水平和有丝分裂。两种特异性的COX-2抑制剂，SC-58125和NS398，也以剂量依赖的方式减弱基线和Lu型转化生长因子刺激的有丝分裂，尽管PG水平在所测试的所有浓度下都降低了90%，但这些发现表明，激活EGFR刺激极化的Hca-7集落29细胞COX-2的产生及其移位、PGs的载体释放和有丝分裂。
Nonsteroidal antiinflammatory drugs reduce the risk of colon cancer, possibly via cyclooxygenase (COX) inhibition, The growth factor inducible COX-2, which is overexpressed in neoplastic colonic tissue, is an attractive target to mediate this effect, Herein we have exploited the ability of a human colon cancer cell line, HCA-7 Colony 29, to polarize when cultured on Transwell (Costar) filters to study COX-2 production and the vectorial release of prostaglandins (PGs), Administration of type a transforming growth factor to the basolateral compartment, in which the epidermal growth factor receptor (EGFR) resides, results in a marked induction of COX-2 immunoreactivity at the base of the cells and the unexpected appearance of COX-2 in the nucleus. The increase in COX-2 protein is associated with a dose- and time-dependent increase in PG levels in the basolateral, but not apical, medium, Amphiregulin is the most abundantly expressed EGFR ligand in these cells, and the protein is present at the basolateral surface, EGFR blockade reduces baseline COX-2 immunoreactivity, PG levels, and mitogenesis in a concentration dependent manner. Two specific COX-2 inhibitors, SC-58125 and NS 398, also, in a dose-dependent manner, attenuate baseline and type Lu transforming growth factor stimulated mitogenesis, although PG levels are decreased >90% at all concentrations of inhibitor tested, These findings show that activation of the EGFR stimulates COX-2 production and its translocation to the nucleus, vectorial release of PGs, and mitogenesis in polarized HCA-7 Colony 29 cells.