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Abrogation of Transforming Growth Factor-/Epidermal Growth Factor Receptor Autocrine Signaling by an RXR-selective Retinoid (LGD1069, Targretin) in Head and Neck Cancer Cell Lines ¹

Departments of Otolaryngology [J. I. S., M. N. L., J. D. H., S. D. D., Q. Z., J. R. G.] and Pharmacology [J. R. G.], University of Pittsburgh School of Medicine, and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [W. W. L.], and Ligand Pharmaceuticals, Inc., San Diego, California 92121 [W. W. L.]

Clinical studies have demonstrated that retinoids, including retinol (Vitamin A) and its synthetic derivatives, can eradicate leukoplakia and suppress the formation of squamous cell carcinoma of the head and neck (SCCHN). Nonselective retinoids have been shown to abrogate transcriptional activation of transforming growth factor- (TGF-) and epidermal growth factor receptor (EGFR), which characterize SCCHN. LGD1069 (Targretin) is a potent RXR-selective retinoic acid agonist with a reduced toxicity profile compared with other nonselective retinoids. We examined the effect of LGD1069 (10 µm) on cellular proliferation and expression of putative intermediate biomarker genes including TGF-, EGFR, and RAR-ß in seven SCCHN cell lines. A quantitative reverse transcription-PCR assay using a novel "primer dropping" method was used to determine expression levels of EGFR, TGF-, and RAR-ß before and after treatment with LGD1069 (10 µM). SCCHN proliferation was reduced by a mean of 50% at 4 days in seven SCCHN cell lines after LGD1069 treatment (P 0.05). EGFR expression levels were decreased by a mean of 58.4% (P = 0.007), TGF- levels were decreased by a mean of 28.8% (P = 0.01), and RAR-ß levels were increased by a mean of 60% (P = 0.03). TGF- stimulation of EGFR is associated with constitutive signal transducer and activator of transcription 3 (Stat3) activation in SCCHN. Abrogation of constitutive Stat3 activation was seen with LGD1069 treatment. These results suggest that an RXR-selective retinoic acid decreases SCCHN proliferation in part by interfering with TGF-/EGFR autocrine signaling.

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