Meloxicam Executes Its Antitumor Effects against Hepatocellular Carcinoma in COX-2-Dependent and -Independent Pathways

被引:44
作者
Dong, Xiaofeng [1 ]
Li, Rui [2 ]
Xiu, Peng [1 ]
Dong, Xuesong [3 ]
Xu, Zongzhen [1 ]
Zhai, Bo [3 ]
Liu, Feng [1 ]
Jiang, Hongchi [3 ]
Sun, Xueying [3 ,4 ]
Li, Jie [1 ]
Qiao, Haiquan [3 ]
机构
[1] Shandong Univ, Qianfoshan Hosp, Dept Gen Surg, Jinan 250100, Peoples R China
[2] Liaocheng Peoples Hosp, Dept Gen Surg, Liaocheng, Peoples R China
[3] Harbin Med Univ, Affiliated Hosp 1, Hepatosplen Surg Ctr, Dept Gen Surg, Harbin, Peoples R China
[4] Univ Auckland, Fac Med & Hlth Sci, Dept Mol Med & Pathol, Auckland 1, New Zealand
来源
PLOS ONE | 2014年 / 9卷 / 03期
关键词
E-CADHERIN; GROWTH-FACTOR; CELL-PROLIFERATION; DOWN-REGULATION; AUTOPHAGY; CYCLOOXYGENASE-2; INVASION; EXPRESSION; APOPTOSIS; MIGRATION;
D O I
10.1371/journal.pone.0092864
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: 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. Methods and Findings: 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. Conclusions: 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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页数:10
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