Retinoid Refractoriness Occurs during Lung Carcinogenesis Despite Functional Retinoid Receptors

Yeul Hong Kim, David F. Dohi, Gil Ro Han, Chang Ping Zou, Nobuhiko Oridate, Garrett L. Walsh, Jonathan C. Nesbitt, Xiao Chun Xu, Waun Ki Hong, Reuben Lotan, Jonathan M. Kurie

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Abstract

Retinoids have demonstrated activity in the prevention of second primary tumors in patients with non-small cell lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to lung carcinogenesis. Using a lung carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we examined all-trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor β (RAR-β) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-β, reflecting the RAR-β expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this lung carcinogenesis model is not intrinsic to the retinoid receptors.

Original languageEnglish
Pages (from-to)5603-5610
Number of pages8
JournalCancer Research
Volume55
Issue number23
Publication statusPublished - 1995 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Kim, Y. H., Dohi, D. F., Han, G. R., Zou, C. P., Oridate, N., Walsh, G. L., Nesbitt, J. C., Xu, X. C., Hong, W. K., Lotan, R., & Kurie, J. M. (1995). Retinoid Refractoriness Occurs during Lung Carcinogenesis Despite Functional Retinoid Receptors. Cancer Research, 55(23), 5603-5610.