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Retinoic acid‐mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27 Kip 1 Expression
Author(s) -
Weber Erich,
Ravi Rajani K.,
Knudsen Erik S.,
Williams Jerry R.,
Dillehay Larry E.,
Nelkin Barry D.,
Kalemkerian Gregory P.,
Feramisco James R.,
Mabry Mack
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990315)80:6<935::aid-ijc21>3.0.co;2-e
Subject(s) - retinoic acid , cancer research , growth inhibition , biology , cyclin dependent kinase , ectopic expression , cell growth , cdk inhibitor , cell cycle , apoptosis , retinoic acid receptor , cell culture , biochemistry , genetics
Abstract Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor β (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 G 1 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. Int. J. Cancer 80:935–943, 1999. © 1999 Wiley‐Liss, Inc.