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

Erich Weber, Rajani K. 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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Abstract

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
Volume80
Issue number6
DOIs
StatePublished - Mar 15 1999

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Retinoic Acid Receptors
Small Cell Lung Carcinoma
Tretinoin
Growth
Cyclin-Dependent Kinase 2
Retinoids
Cell Cycle Checkpoints
Lung Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

In: International Journal of Cancer, Vol. 80, No. 6, 15.03.1999, p. 935-943.

Research output: Contribution to journalArticle

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. / Retinoic acid-mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27(Kip1) expression. In: International Journal of Cancer. 1999 ; Vol. 80, No. 6. pp. 935-943.
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abstract = "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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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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