Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl) retinamide inhibitory effects in breast cancer cells
Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl) retinamide inhibitory effects in breast cancer cells
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DOI：
10.1038/labinvest.3700339
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发表时间：
2005-11-01
影响因子：
5
通讯作者：
Symmans, WF
中科院分区：
文献类型：
--
作者：
Tari, AM;Simeone, AM;Symmans, WF
大约 30 - 40% 的雌激素受体 α (ER α) 阳性乳腺肿瘤表达高水平的环氧合酶-2 (COX-2) 蛋白，而这些高水平与乳腺癌患者的较差预后相关。我们推测高水平的COX-2会诱导ERα阳性乳腺肿瘤产生耐药性，从而降低此类肿瘤患者的生存率。表达高水平 COX-2 的人类乳腺癌细胞系通常为 ER α 阴性。为了确定COX-2是否诱导耐药性，将编码COX-2基因的质粒稳定转染到ERα阳性MCF-7人乳腺癌细胞（MCF-7/COX-2）中。 MCF-7/COX-2 细胞对选择性雌激素受体调节剂他莫昔芬有耐药性，但对其类似物雷洛昔芬没有耐药性。 MCF-7/COX-2 细胞还对类视黄醇 N-(4-羟苯基) 视黄酰胺 (4-HPR) 具有耐药性，但对其类似物全反式视黄酸不具有耐药性。相反，MCF-7/COX-2细胞对阿霉素和紫杉醇的敏感性与亲代MCF-7细胞相似。然后我们确定哪种 COX-2 产物、前列腺素 E-2 (PGE(2)) 或前列腺素 F-2 α 参与 COX-2 介导的耐药性。 PGE(2)（而非 PGF(2α））可阻断他莫昔芬和 4-HPR 的抗增殖作用。激活 PGE(2) 受体及其下游激酶效应器（蛋白激酶 A 和 C）的激动剂也可阻断这些药物的生长抑制作用。据报道，COX-2 转基因小鼠的乳腺肿瘤和具有高水平 COX-2 的人结肠癌细胞系中 Bcl-2 和 Bcl-X-L 蛋白水平增加。然而，我们没有观察到 COX-2 或 PGE(2) 诱导的 Bcl-2、Bcl-X-L 或 Bax 表达有任何变化。在这里，我们报告了新的发现，即COX-2利用PGE(2)刺激蛋白激酶A和C的活性，选择性诱导ERα阳性乳腺癌细胞对他莫昔芬和4-HPR耐药。
Approximately 30 - 40% of estrogen receptor alpha (ER alpha)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ER alpha-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ER alpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ER alpha-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E-2 ( PGE(2)) or prostaglandin F-2 alpha is involved in the COX-2-mediated drug resistance. PGE(2), but not PGF(2 alpha), blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE(2) receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-X-L proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-X-L, or Bax expression induced by COX-2 or PGE(2). Here we report the novel findings that COX-2 uses PGE(2) to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ER alpha-positive breast cancer cells.