COX-2-Dependent and COX-2-Independent Mode of Action of Celecoxib in Human Liver Cancer Cells
COX-2-Dependent and COX-2-Independent Mode of Action of Celecoxib in Human Liver Cancer Cells
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DOI：
10.1089/omi.2010.0092
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发表时间：
2011-06-01
影响因子：
3.3
通讯作者：
Montalto, Giuseppe
中科院分区：
文献类型：
--
作者：
Cervello, Melchiorre;Bachvarov, Dimcho;Montalto, Giuseppe
塞来昔布（西乐葆（（R）），辉瑞）是一种选择性环氧合酶-2（考克斯-2）抑制剂，具有化学预防和抗肿瘤作用。然而，现在众所周知塞来昔布具有几种不依赖于考克斯-2的活性。为了更好地了解塞来昔布抗肿瘤活性的考克斯-2非依赖性分子机制，我们使用微阵列分析研究了塞来昔布处理的考克斯-2阳性（Huh 7）和考克斯-2阴性（HepG 2）肝癌细胞系的表达谱。塞来昔布处理导致Huh 7和HepG 2细胞中240和403转录本的表达水平分别显著改变。通过半定量RT-PCR对所选基因进行微阵列结果的确认。使用独创性途径分析和探索生物关联网络对塞来昔布影响的转录物进行的途径/功能分析显示，塞来昔布调节参与各种细胞过程的许多基因的表达，包括细胞死亡、细胞生长和增殖、脂质代谢和能量转换。其中一些过程在两种HCC细胞系中是共同的，并且似乎与NF-κ B信号传导偶联，而其他过程是细胞特异性的，并且可能与相应细胞系中存在或不存在考克斯-2活性有关。从我们的分析中出现了许多新的基因，这些基因以前没有报道过受到塞来昔布的影响。对选定的塞来昔布反应基因的进一步研究将确定它们是否可以作为HCC更有效治疗策略的潜在分子靶点。
Celecoxib (Celebrex((R)), Pfizer) is a selective cyclooxygenase-2 (COX-2) inhibitor with chemopreventive and antitumor effects. However, it is now well known that celecoxib has several COX-2-independent activities. To better understand COX-2-independent molecular mechanisms underlying the antitumor activity of celecoxib, we investigated the expression profile of the celecoxib-treated COX-2-positive (Huh7) and COX-2-negative (HepG2) liver cancer cell lines, using microarray analysis. Celecoxib treatment resulted in significantly altered expression levels of 240 and 403 transcripts in Huh7 and HepG2 cells, respectively. Confirmation of the microarray results was performed for selected genes by semiquantitative RT-PCR. A pathway/functional analysis of celecoxib-affected transcripts, using ingenuity pathway analysis and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including cell death, cellular growth and proliferation, lipid metabolism, and energy turnover. Some of these processes were common for both HCC cell lines and seem to be coupled with NF-kappa B signaling, while others were cell-specific and possibly linked to the presence or the absence of COX-2 activity in the corresponding cell line. Many novel genes emerged from our analyses that were not previously reported to be affected by celecoxib. Further studies on selected celecoxib-responsive genes will establish if they may serve as potential molecular targets for more effective therapeutic strategies in HCC.