title: Meloxicam executes its antitumor effects against hepatocellular carcinoma in COX-2- dependent and -independent pathways.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Liaocheng People's Hospital, Liaocheng, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Zongzhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Qiao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D000077239:Meloxicam; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D016861:Cyclooxygenase Inhibitors; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013843:Thiazines; D013844:Thiazoles; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D000077239:Meloxicam