PMID- 15825163
OWN - NLM
STAT- MEDLINE
DCOM- 20050824
LR  - 20160303
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 116
IP  - 4
DP  - 2005 Sep 10
TI  - COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma 
      cells through activation of Erk: involvement of Sp1 and AP-1 sites.
PG  - 536-46
AB  - Tumor cell expression of COX-2 has been implicated in the progression of murine 
      and human lung cancer. Inhibition of COX-2 by nonsteroidal antiinflammatory drugs 
      reduces the risk of cancer development in humans and suppresses tumor growth in 
      animal models. However, the underlying mechanisms for this beneficial effect are 
      not fully understood. Here we explore the potential link between the anticancer 
      effects of COX-2 inhibitors and the expression of the integrin alpha5beta1. 
      Expression of this integrin in carcinoma cells is associated with invasiveness 
      and malignant progression. This, together with our studies showing that 
      fibronectin, the ligand of alpha5beta1, stimulates the growth of human lung 
      carcinoma cells, and that this effect is mediated through alpha5beta1-dependent 
      signals, has prompted us to examine the effects of COX-2 inhibitors on 
      alpha5beta1 expression in human non small cell lung carcinoma (NSCLC) cells. We 
      found that the selective COX-2 inhibitors NS398 and Nimesulide decreased mRNA 
      expression and protein production of the integrin alpha5 subunit. This effect was 
      associated with inhibition of NSCLC cell adhesion to fibronectin. The COX-2 
      inhibitors triggered the phosphorylation of extracellular signal-regulated kinase 
      (Erk) in a time-dependent manner, and the inhibitor of Mek-1/Erk PD98095 
      prevented their inhibitory effects on integrin alpha5 expression. Transient 
      transfection assays showed that the COX-2 inhibitors affected integrin alpha5 
      gene transcription by acting between -92 to -41 bp of the human integrin alpha5 
      gene promoter. Gel mobility shift assays showed that the COX-2 inhibitors 
      increased Sp1 DNA binding, but decreased that of AP-1. These effects were 
      accompanied by an increase in Sp1 protein and a decrease in c-Jun protein 
      expression, as well as inhibition of SAPK/JNK phosphorylation. The Sp1 inhibitor, 
      Mithramycin A, also blocked the inhibitory effect of the COX-2 inhibitors on 
      alpha5 expression and promoter activity. Overall, these findings suggest that 
      COX-2 inhibitors suppress alpha5beta1 integrin expression in NSCLC through 
      effects on integrin alpha5 gene transcription mediated by Erk activation, 
      increased Sp1, decreased AP-1 DNA binding and inactivation of SAPK/JNK signals. 
      Our observations unveil a new mechanism of action against NSCLC for COX-2 
      inhibitors that relates to regulation of integrin alpha5 gene expression and, 
      consequently, recognition of extracellular matrices (i.e., fibronectin) by tumor 
      cells. (c) 2005 Wiley-Liss, Inc.
FAU - Han, ShouWei
AU  - Han S
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. 
      shan2@emory.edu
FAU - Roman, Jesse
AU  - Roman J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Retracted Publication
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Fibronectins)
RN  - 0 (Immunoglobulins)
RN  - 0 (Integrin alpha5)
RN  - 0 (Nitrobenzenes)
RN  - 0 (SP1 antigen)
RN  - 0 (Sulfonamides)
RN  - 123653-11-2 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - V4TKW1454M (nimesulide)
SB  - IM
RIN - Int J Cancer. 2015 Oct 15;137(8):2041. PMID: 26252813
MH  - Carcinoma, Non-Small-Cell Lung/genetics/*pathology
MH  - Cell Adhesion
MH  - Cyclooxygenase Inhibitors/*pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/physiology
MH  - Fibronectins
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Immunoglobulins/physiology
MH  - Integrin alpha5/*biosynthesis
MH  - JNK Mitogen-Activated Protein Kinases/physiology
MH  - Lung Neoplasms/genetics/*pathology
MH  - MAP Kinase Kinase 4/physiology
MH  - Mitogen-Activated Protein Kinase Kinases/physiology
MH  - Nitrobenzenes/*pharmacology
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Sulfonamides/*pharmacology
MH  - Transcription, Genetic
MH  - Transfection
MH  - Tumor Cells, Cultured
EDAT- 2005/04/13 09:00
MHDA- 2005/08/25 09:00
CRDT- 2005/04/13 09:00
PHST- 2005/04/13 09:00 [pubmed]
PHST- 2005/08/25 09:00 [medline]
PHST- 2005/04/13 09:00 [entrez]
AID - 10.1002/ijc.21125 [doi]
PST - ppublish
SO  - Int J Cancer. 2005 Sep 10;116(4):536-46. doi: 10.1002/ijc.21125.