TY - JOUR
T1 - Retinoic acid-mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27(Kip1) expression
AU - Weber, Erich
AU - Ravi, Rajani K.
AU - Knudsen, Erik S.
AU - Williams, Jerry R.
AU - Dillehay, Larry E.
AU - Nelkin, Barry D.
AU - Kalemkerian, Gregory P.
AU - Feramisco, James R.
AU - Mabry, Mack
PY - 1999/3/15
Y1 - 1999/3/15
N2 - 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.
AB - 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.
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U2 - 10.1002/(SICI)1097-0215(19990315)80:6<935::AID-IJC21>3.0.CO;2-E
DO - 10.1002/(SICI)1097-0215(19990315)80:6<935::AID-IJC21>3.0.CO;2-E
M3 - Article
C2 - 10074929
AN - SCOPUS:0033559524
SN - 0020-7136
VL - 80
SP - 935
EP - 943
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 6
ER -