Meloxicam executes its antitumor effects against hepatocellular carcinoma in COX-2- dependent and -independent pathways.
Meloxicam executes its antitumor effects against hepatocellular carcinoma in COX-2- dependent and -independent pathways.
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DOI：
10.1371/journal.pone.0092864
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Qiao H
中科院分区：
文献类型：
--
作者：
Dong X;Li R;Xiu P;Dong X;Xu Z;Zhai B;Liu F;Jiang H;Sun X;Li J;Qiao H
环氧合酶(COX)-2在包括肝细胞癌在内的多种肿瘤中均有过表达。美洛昔康是一种选择性的COX-2抑制剂，已显示出对肝癌的潜在治疗作用，但其抗癌活性的机制尚不清楚。美洛昔康通过上调E-钙粘蛋白的表达和下调基质金属蛋白酶-2的表达，抑制高表达COX-2的人肝癌细胞的迁移、侵袭、黏附和集落形成能力。美洛昔康通过上调促凋亡蛋白bax和Fas-L，下调抗凋亡蛋白Survivin和髓系白血病-1(Mcl-1)，抑制AKT的磷酸化，从而诱导细胞凋亡。加入COX-2的主要产物前列腺素E_2(PGE_2)可阻断美洛昔康对Survivin和髓系白血病细胞白血病-1(McL-1)表达的影响，但不能阻断bax和Fas-L的表达，表明美洛昔康通过COX-2依赖和非依赖途径诱导细胞凋亡。美洛昔康还通过上调Beclin 1和轻链3-II诱导细胞自噬。3-甲基腺嘌呤和氯喹对细胞自噬的特异性抑制作用不明显，但可通过进一步上调Bax的表达而增强美洛昔康的促凋亡作用。美洛昔康通过靶向COX-2/MMP2/E-cadherin、AKT、COX-2依赖和非依赖途径中的凋亡和自噬途径发挥抗肿瘤作用，抑制细胞自噬有助于克服对美洛昔康诱导的肝癌细胞凋亡的抵抗。
Cyclooxygenase (COX)-2 is overexpressed in many types of cancers including hepatocellular carcinoma (HCC). Meloxicam, a selective COX-2 inhibitor, has shown potential therapeutic effects against HCC, but the mechanisms accounting for its anti-cancer activities remain unclear. Meloxicam inhibited the ability of human HCC cells expressing higher levels of COX-2 to migrate, invade, adhere and form colonies through upregulating the expression of E-cadherin and downregulating the expression of matrix metalloproteinase (MMP) -2. Meloxicam induced cell apoptosis by upregulating pro-apoptotic proteins including Bax and Fas-L, and downregulating anti-apoptotic proteins including survivin and myeloid cell leukemia-1 (Mcl-1), through inhibiting phosphorylation of AKT. Addition of prostaglandin E2 (PGE2), the major product of COX-2, could abrogate the effects of meloxicam on the expression of survivin and myeloid cell leukemia-1 (Mcl-1), but not Bax and Fas-L, indicating that meloxicam induces cell apoptosis via both COX-2-dependent and -independent pathways. Meloxicam also induced cell autophagy by upregulating Beclin 1 and light chain 3-II. Specific inhibition of autophagy by 3-methyladenine and chloroquine had little effect on cell apoptosis but could enhance the pro-apoptotic effects of meloxicam by further upregulating the expression of Bax. Meloxicam executes its antitumor effects by targeting the COX-2/MMP-2/E-cadherin, AKT, apoptotic and autophagic pathways in COX-2-dependent and -independent pathways, and inhibition of cell autophagy could help to overcome the resistance to meloxicam-induced apoptosis in HCC.
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