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Synergistic effects of RXRα and PPARγ ligands to inhibit growth in human colon cancer cells—phosphorylated RXRα is a critical target for colon cancer management
  1. Kenji Yamazaki1,
  2. Masahito Shimizu1,
  3. Masataka Okuno1,
  4. Rie Matsushima-Nishiwaki1,
  5. Nobuhiro Kanemura1,
  6. Hiroshi Araki1,
  7. Hisashi Tsurumi1,
  8. Soichi Kojima2,
  9. I Bernard Weinstein3,
  10. Hisataka Moriwaki1
  1. 1
    Department of Medicine, Gifu University School of Medicine, Gifu, Japan
  2. 2
    Molecular Cellular Pathology Research Unit, Discovery Research Institute, Riken, Wako, Japan
  3. 3
    Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, New York, USA
  1. Masahito Shimizu, Department of Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan; shimim-gif{at}umin.ac.jp

Abstract

Background and aims: The activation of the peroxisome proliferator-activated receptor γ (PPARγ) 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 RXRα (p-RXRα) interfered with its signalling and promoted the growth of hepatoma cells. In this study the effects of p-RXRα on the ability of RXRα and PPARγ ligands to inhibit growth in colon cancer cells was examined.

Methods: The effects of the combination of the PPARγ ligand ciglitazone and the RXRα lignad 9-cis-retinoic acid (RA) on inhibition of cell growth in Caco2 human colon cancer cells which express high levels of p-RXRα protein were examined

Results: The RXRα protein was phospholylated and also accumulated in human colon cancer tissue samples as well as human colon cancer cell lines. When the phosphorylation of RXRα was inhibited by the MEK inhibitor PD98059 or by transfection with a point-mutated RXRα, 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 RXRα due to phosphorylation is associated with colorectal cancer. Therefore, the inhibition of phosphorylation of RXRα and the activation of the RXR–PPARγ heterodimer by their respective ligands may be useful in the chemoprevention and/or treatment of colorectal cancer.

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Footnotes

  • This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (No. 17015016 to HM and No. 18790457 to MS).

  • Competing interests: None.

  • Abbreviations:
    cig
    ciglitazone
    COX
    cyclo-oxygenase
    FCS
    fetal calf serum
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MAPK
    mitogen-activated protein kinase
    PPAR
    peroxisome proliferator-activated receptor
    PPRE
    peroxisome proliferator-responsive element
    p-RXRα
    phosphorylated RXR, retinoid X receptor α
    RA
    retinoic acid
    RT-PCR
    reverse transcription-PCR
    RXR
    retinoid X receptor
    TNBS
    2,4,6-trinitrobenzene sulphonic acid
    TUNEL
    terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling

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