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 language||English (US)|
|Number of pages||9|
|Journal||International Journal of Cancer|
|State||Published - Mar 15 1999|
ASJC Scopus subject areas
- Cancer Research