Responsiveness to the retinoic acid receptor-selective retinoid LGD1550 correlates with abrogation of transforming growth factor alpha/epidermal growth factor receptor autocrine signaling in head and neck squamous carcinoma cells.
OBJECTIVE
The use of retinoids to prevent and/or treat cancers, including head and neck squamous cell carcinoma (HNSCC), has been limited by the development of resistance and unwanted side effects. Receptor-selective retinoids are potentially less toxic than nonselective compounds. The present investigation was undertaken to determine the mechanism of responsiveness to an retinoic acid receptor-selective retinoid (LGD1550) that has shown antitumor efficacy in a xenograft model of HNSCC.


METHODS
A series of HNSCC cell lines were characterized with respect to proliferation and apoptosis after LGD1550 treatment. Relative responsiveness to LGD1550 was examined with respect to modulation of epidermal growth factor receptor (EGFR) signaling pathways.


RESULTS
Cells were either growth inhibited and underwent apoptosis or were resistant to treatment with this compound. Retinoids have been shown to decrease the gene transcription rates of transforming growth factor (TGF)-alpha and EGFR in HNSCC. LGD1550 responsiveness was accompanied by decreased expression of TGF-alpha, EGFR, and modulation of EGFR signaling pathways, including signal transducers and activators of transcriptions and mitogen-activated protein kinase. In contrast, EGFR autocrine signaling pathways were not altered in HNSCC cells that were resistant to the growth inhibitory effects of LGD1550.


CONCLUSIONS
These results suggest that there is a correlation between the efficacy of receptor-selective retinoids and modulation of TGF-alpha/EGFR signaling in HNSCC. Therefore, alterations of these signaling pathways may serve as a biomarker of clinical response.
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077610:Bexarotene; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014183:Transplantation, Heterologous
D016588:Anticarcinogenic Agents; D005231:Fatty Acids, Unsaturated; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C062198:octa-2,4,6-trienoic acid; D000077610:Bexarotene; D066246:ErbB Receptors