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Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids

Oncogene volume 19, pages 1457–1465 (2000)Cite this article

Abstract

Retinoids have been shown to inhibit the growth of many human tumor cells including breast, ovarian and squamous cell carcinoma (SCC). While the exact mechanism of retinoid mediated growth suppression is not known, a role for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been established in both the breast and ovarian tumor cell models. We set out to determine if modulation of RAR/RXR function would alter the retinoid sensitivity of oral SCC cells. We found that the growth of SCC cells was significantly inhibited by treatment with either all-trans-retinoic acid (trans-RA) or the synthetic, conformationally restricted RARγ selective retinoids MM11254 and MM11389. In order to demonstrate a role for RAR/RXR function in this process, stable oral SCC cell clones constitutively overexpressing the dominant negative mutant RARβ2 (R269Q) were prepared and shown to exhibit reduced RAR/RXR transcriptional transactivation activity. We found that oral SCC cells exhibiting reduced RAR/RXR function became resistant to growth inhibition by all-trans-RA, MM11254 and MM11389. Likewise, treatment of oral SCC cells with the RARγ antagonist MM11253 was found to block the ability of MM11254 and MM11389 to inhibit SCC cell growth. Thus, modulation of RAR function through the use of RAR-γ selective agonists, an RAR-γ selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCC cells to retinoids.

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Abbreviations

SCC:

squamous cell carcinoma

RARs:

retinoic acid receptors

RXRs:

retinoid X receptors

all-trans-RA:

all-trans-retinoic acid

PAGE:

polyacrylamide gel electrophoresis

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Acknowledgements

This work was supported by grants from the National Institutes of Health (DK 49045 and CA 64945) to KJ Soprano and CA 51993 to MI Dawson. We thank F Hoffman La-Roche and Co. for the retinoic acid used in these studies. We thank Ms Dongmei Zhang and Mr William F Holmes for technical assistance and Ms Man Yu for helping with manuscript preparation.

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Authors and Affiliations

  1. Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, 19140, Pennsylvania, PA, USA

    Quan Le, Dianne Robert Soprano & Kenneth J Soprano

  2. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, 19140, Pennsylvania, PA, USA

    Kenneth J Soprano

  3. Department of Biochemistry, Temple University School of Medicine, Philadelphia, 19140, Pennsylvania, PA, USA

    Dianne Robert Soprano

  4. Department of Medicinal Chemistry, Molecular Medicine Research Institute, Mountain View, California, 94043, CA, USA

    Marcia I Dawson

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Le, Q., Dawson, M., Soprano, D. et al. Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids. Oncogene 19, 1457–1465 (2000). https://doi.org/10.1038/sj.onc.1203436

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