Retinoic acid-mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27(Kip1) expression

Erich Weber, Rajani Ravi, Erik S. Knudsen, Jerry R. Williams, Larry E. Dillehay, Barry D Nelkin, Gregory P. Kalemkerian, James R. Feramisco, Mack Mabry

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Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor 13 (RAR-β) and are resistant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-β in the growth regulation of SCLC by retinoids, we restored RAR-β expression in RAR-β-negative H209 SCLC cells by retroviral transduction (H209-RAR-β). We found that H209-RAR-β, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA- treated H209-RAR-β cells arrested in G1 and displayed reduced L-myc expression and cyclin-dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209-RAR-β cells was also accompanied by increased expression of the cdk inhibitor p27(Kip1), whereas no differences in the expression of L-myc or p27(Kip1) were detected upon RA treatment of parental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which express endogenous RAR-β, was also associated with reduced c-myc and increased p27(Kip1) expression. We found that ectopic expression of p27(Kip1) induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209-RAR-β cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR-β gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27(Kip1) may represent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-β.

Original languageEnglish (US)
Pages (from-to)935-943
Number of pages9
JournalInternational Journal of Cancer
Issue number6
StatePublished - Mar 15 1999


ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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