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

Human lung cancer cells, including small cell lung carcinoma (SCLC), freque ntly lose expression of retinoic acid receptor beta (RAR-beta) and are resi stant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-beta in the growth regulation of SCLC by retinoi ds, we restored RAR-beta expression in RAR-beta-negative H209 SCLC cells by retroviral transduction (H209-RAR-beta), We found that H209-RAR-beta, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA- treated H209-RAR-beta cells arrested in G(1) and displayed reduced L-myc ex pression and cyclin dependent kinase 2 (cdk2) activity compared with untrea ted cells, RA treatment of H209-RAR-beta cells was also accompanied by incr eased 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 par ental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which exp ress endogenous RAR-beta, was also associated with reduced c-myc and increa sed p27(Kip1) expression. We found that ectopic expression of p27(Kip1) ind uced growth inhibition in both H209 and H82 cells, and that sustained myc e xpression in H209-RAR-beta cells promoted the induction of apoptosis upon R A addition, Our observations indicate that RAR-beta gene transfer can resto re RA sensitivity in SCLC cells and suggest that myc and p27(Kip1) may repr esent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-beta. Int. J. Cancer 80:935-943, 1999. (C) 1999 Wiley-Liss, Inc.