Stage‐specific effect of N‐(4‐hydroxyphenyl)retinamide on cell growth in squamous cell carcinogenesis

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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 I7 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.