PMID- 17604322
OWN - NLM
STAT- MEDLINE
DCOM- 20071120
LR  - 20220224
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 56
IP  - 11
DP  - 2007 Nov
TI  - Synergistic effects of RXR alpha and PPAR gamma ligands to inhibit growth in 
      human colon cancer cells--phosphorylated RXR alpha is a critical target for colon 
      cancer management.
PG  - 1557-63
AB  - BACKGROUND AND AIMS: The activation of the peroxisome proliferator-activated 
      receptor gamma (PPAR gamma) that forms heterodimers with retinoid X receptors 
      (RXRs) elicits an antineoplastic effect on colorectal cancer. It was previously 
      reported that the accumulation of the non-functional phosphorylated form of RXR 
      alpha (p-RXR alpha) interfered with its signalling and promoted the growth of 
      hepatoma cells. In this study the effects of p-RXR alpha on the ability of RXR 
      alpha and PPAR gamma ligands to inhibit growth in colon cancer cells was 
      examined. METHODS: The effects of the combination of the PPAR gamma ligand 
      ciglitazone and the RXR alpha lignad 9-cis-retinoic acid (RA) on inhibition of 
      cell growth in Caco2 human colon cancer cells which express high levels of p-RXR 
      alpha protein were examined. RESULTS: The RXR alpha protein was phospholylated 
      and also accumulated in human colon cancer tissue samples as well as human colon 
      cancer cell lines. When the phosphorylation of RXR alpha was inhibited by the MEK 
      inhibitor PD98059 or by transfection with a point-mutated RXR alpha, which 
      mimicked the unphosphorylated form, the combination of 9-cisRA and ciglitazone 
      synergistically inhibited the cell growth and induced apoptosis. The combined 
      treatment with these agents also caused a decrease in the expression levels of 
      both cyclo-oxygenase-2 (COX-2) and c-Jun proteins and mRNAs. Reporter assays 
      indicated that this combination induced the transcriptional activity of the 
      peroxisome proliferator-responsive element promoter and also inhibited that of 
      the AP-1 promoter. CONCLUSION: A malfunction of RXR alpha due to phosphorylation 
      is associated with colorectal cancer. Therefore, the inhibition of 
      phosphorylation of RX R alpha and the activation of the RXR-PPAR gamma 
      heterodimer by their respective ligands may be useful in the chemoprevention 
      and/or treatment of colorectal cancer.
FAU - Yamazaki, Kenji
AU  - Yamazaki K
AD  - Department of Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 
      501-1194, Japan.
FAU - Shimizu, Masahito
AU  - Shimizu M
FAU - Okuno, Masataka
AU  - Okuno M
FAU - Matsushima-Nishiwaki, Rie
AU  - Matsushima-Nishiwaki R
FAU - Kanemura, Nobuhiro
AU  - Kanemura N
FAU - Araki, Hiroshi
AU  - Araki H
FAU - Tsurumi, Hisashi
AU  - Tsurumi H
FAU - Kojima, Soichi
AU  - Kojima S
FAU - Weinstein, I Bernard
AU  - Weinstein IB
FAU - Moriwaki, Hisataka
AU  - Moriwaki H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070629
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Growth Inhibitors)
RN  - 0 (PPAR gamma)
RN  - 0 (Retinoid X Receptor alpha)
RN  - 0 (Thiazolidinediones)
RN  - 5688UTC01R (Tretinoin)
RN  - U8QXS1WU8G (ciglitazone)
SB  - IM
MH  - Caco-2 Cells
MH  - Colonic Neoplasms/*metabolism/pathology/therapy
MH  - Drug Synergism
MH  - Female
MH  - Growth Inhibitors
MH  - Humans
MH  - Male
MH  - PPAR gamma/*metabolism
MH  - Phosphorylation
MH  - Retinoid X Receptor alpha/*metabolism
MH  - Thiazolidinediones/*pharmacology
MH  - Tretinoin/*pharmacology
PMC - PMC2095663
COIS- Competing interests: None.
EDAT- 2007/07/03 09:00
MHDA- 2007/12/06 09:00
PMCR- 2010/11/01
CRDT- 2007/07/03 09:00
PHST- 2007/07/03 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/07/03 09:00 [entrez]
PHST- 2010/11/01 00:00 [pmc-release]
AID - gut.2007.129858 [pii]
AID - gt129858 [pii]
AID - 10.1136/gut.2007.129858 [doi]
PST - ppublish
SO  - Gut. 2007 Nov;56(11):1557-63. doi: 10.1136/gut.2007.129858. Epub 2007 Jun 29.