Mechanism of all-trans-retinoic acid-mediated L-myc gene regulation in small cell lung cancer.
The L-myc oncogene is commonly expressed in small cell lung cancer (SCLC) cells and is associated with SCLC cells with a high level of neuroendocrine differentiation and a relatively low proliferative index. We have previously reported that all-trans-retinoic acid (RA) inhibits the growth of NCI-H82 SCLC cells in association with increased neuroendocrine differentiation, increased L-myc gene expression and decreased c-myc gene expression. In the present report, the mechanism of RA-mediated L-myc up-regulation in NCI-H82 SCLC cells was determined by analysing transcriptional and post-transcriptional control of L-myc gene expression. Increases in steady-state levels of L-myc mRNA occurred in a dose-dependent manner after exposure to RA at a time-point prior to discernible changes in cellular morphology or growth. By nuclear run-on analysis, there was a clear increase in L-myc transcript initiation in NCI-H82 cells treated with 1 microM RA, but no alteration was noted in the baseline degree of transcript attenuation when compared to control cells. L-myc transcript half-life remained unchanged after exposure to 1 microM RA, indicating that post-transcriptional regulation is not a major factor in the control of L-myc gene expression. A marked dose-dependent increase in RARbeta expression was also demonstrated in RA-treated NCI-H82 cells. We conclude that RA-mediated up-regulation of L-myc gene expression occurs through stimulation of transcript initiation and that the biological effects of RA in SCLC cells may be mediated through RARbeta-dependent pathways.
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Division of Hematology and Oncology, Wayne State University, Detroit, Michigan 48201, USA.
Campau
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Slusher
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Jasti
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Mabry
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Kalemkerian
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D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin; D003513:Cycloheximide