Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines.
Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines.
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DOI：
10.1016/j.jss.2010.04.061
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Lucci A
中科院分区：
文献类型：
--
作者：
Singh B;Irving LR;Tai K;Lucci A
环氧合酶-2（考克斯-2）在乳腺癌的发生、发展和转移中起重要作用。有效的治疗靶向考克斯-2需要了解肿瘤是否对考克斯-2成瘾，以及我们是否可以对抗抗考克斯-2治疗的潜在抗性。在此，我们测试了塞来昔布耐药性涉及选择过表达考克斯-2的癌细胞的假设。我们通过在塞来昔布存在下培养两种转移性细胞系，SUM 149炎性乳腺癌（IBC）细胞系和MDA-MB-231-BSC 60细胞系，选择塞来昔布耐药（CER）变异体。我们通过蛋白质印迹法测定了亲本细胞系及其CER变体中考克斯-2蛋白及其网络组分Bcl-2、Bcl-xL和Bax的相对水平。为了确定塞来昔布耐药是否会增加致瘤性，我们进行了体外克隆形成试验。我们使用双样本t检验确定组间差异的统计学显著性。塞来昔布耐药细胞系SUM 149-CER和BSC 60-CER产生的考克斯-2蛋白水平显著高于其亲本对应物（p < 0.05）。CER变体产生降低水平的促凋亡蛋白Bax（两种细胞系）和增加水平的抗凋亡蛋白Bcl-2（BSC 60）或Bcl-xL（SUM 149）。重要的是，CER变体具有比其亲本细胞系显著更高的克隆形成性（p < 0.05）。siRNA介导的考克斯-2基因敲低导致SUM 149-CER细胞系的克隆形成能力和Bcl-xL和Bcl-2蛋白水平显著降低，从而支持我们的假设。乳腺癌细胞系中存在的塞来昔布耐药变异细胞过表达考克斯-2，其与生存途径和克隆形成密切相关。由于考克斯-2在侵袭性的变异癌细胞中是重要的，因此它代表了良好的治疗靶点。
Cyclooxygenase-2 (COX-2) plays a key role in breast cancer progression and metastasis. Effective therapeutic targeting of COX-2 would require the knowledge of whether a tumor is addicted to COX-2, and if we can counter the potential resistance to anti-COX-2 therapy. Herein we tested the hypothesis that celecoxib-resistance involves selection of cancer cells that overexpress COX-2. We selected celecoxib-resistant (CER) variants from two metastatic cell lines, SUM149 inflammatory breast cancer (IBC) cell line and MDA-MB-231-BSC60 cell line, by culturing them in the presence of celecoxib. We measured the relative levels of COX-2 protein and its network components Bcl-2, Bcl-xL, and Bax in the parental cell lines and their CER variants by western blotting. To determine whether celecoxib-resistance would increase tumorigenicity, we performed an in vitro clonogenicity assay. We determined the statistical significance of differences between the groups using the two-sample t-test. Both the celecoxib-resistant cell lines SUM149-CER and BSC60-CER produced significantly higher levels of COX-2 protein than their parental counterparts (p < 0.05). The CER variants produced a reduced level of pro-apoptosis protein Bax (both cell lines) and increased levels of anti-apoptosis proteins Bcl-2 (BSC60) or Bcl-xL (SUM149). Importantly, the CER variants had significantly higher clonogenicity than their parental cell lines (p < 0.05). The siRNA-mediated COX-2 knockdown in SUM149-CER cell line resulted in a significant decrease in clonogenicity and in Bcl-xL and Bcl-2 protein levels, thus supporting our hypothesis. Celecoxib-resistant variant cells present in breast cancer cell lines overexpress COX-2, which is robustly linked with survival pathways and clonogenicity. Since COX-2 is important in the variant cancer cells of aggressive nature, it represents a good therapeutic target.
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DOI：
10.1158/1078-0432.ccr-08-0958
发表时间：
2008-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Mustafa A;Kruger WD
通讯作者：
Kruger WD
NF-KAPPA B基因在炎症性乳腺癌中具有重要作用。
影响因子：
3.8
作者：
Lerebours F;Vacher S;Andrieu C;Espie M;Marty M;Lidereau R;Bieche I
通讯作者：
Bieche I
DOI：
10.1186/bcr1678
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Howe LR
通讯作者：
Howe LR
影响因子：
2.2
作者：
Singh, B;Berry, JA;Lucci, A
通讯作者：
Lucci, A
影响因子：
2.2
作者：
Singh, Balraj;Cook, Kendra R.;Lucci, Anthony
通讯作者：
Lucci, Anthony