Stage-Specific Effect of N-(4-Hydroxyphenyl)Retinamide on Cell Growth in Squamous Cell Carcinogenesis

Mohamed Kabbout, Asma Hatoum, Ghada Abou-Lteif, Imane Chakroun, Fadia R. Homaidan, Nadine Darwiche

Research output: Contribution to journalArticle

Abstract

Squamous cell carcinoma (SCC) is the most prevalent form of epithelial cancer. SCC results when normal epithelial cells undergo multiple neoplastic changes that culminate in the evolution of an invasive cancer. Retinoids are commonly used as chemopreventive and treatment agents in skin cancer; however, SCC progression is accompanied by a gradual loss of retinoid responsiveness. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) has shown promising anti-neoplastic activity in a variety of tumor cells, including those that are resistant to all-trans retinoic acid (t-RA). We investigated the effect of HPR on growth and apoptosis of squamous cells at different stages of carcinogenesis. We then determined if retinoic acid receptor (RAR) overexpression affected the outcome of HPR treatment. To model SCC malignant progression, we used a panel of murine keratinocytes representing different stages of squamous cell carcinogenesis. This panel consisted of primary keratinocytes, SP1 and 308 papilloma cell lines, the PAM-212 squamous carcinoma cell line, and the spindle 17 cell line. With the exception of the primary keratinocytes, all cells were unresponsive to t-RA treatment. Pharmacological concentrations of HPR were non-cytotoxic to all keratinocytes tested and HPR sensitivity was stage-dependent, with the papilloma cell lines being the most sensitive, and the spindle cells being the most resistant. Overexpression of RARγ in SP1 papilloma cells enhanced growth suppression and apoptosis induction by HPR. HPR-induced growth suppression was accompanied by a simultaneous block in the G1 phase of the cell cycle in RAR-transduced and control SP1 cells and differential regulation of cell cycle and apoptotic mediators.

Original languageEnglish (US)
Pages (from-to)12-23
Number of pages12
JournalMolecular Carcinogenesis
Volume40
Issue number1
DOIs
StatePublished - May 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Cell-cycle arrest
  • Neoplastic keratinocytes
  • Retinoid receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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