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Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells

Abstract

Although originally synthesized as an anti-estrogen, tamoxifen (Tam) was found to be able to inhibit proliferation of estrogen receptor (ER)-negative cancer cells in vitro. However, the molecular basis of such ER-independent growth inhibition is largely unknown. We have previously demonstrated that Tam induces p21WAF1 and p27KIP1 expression in human lung cancer cells which lack ER-α and -β. We found that Tam induced p21WAF1 expression via transcriptional activation. In order to determine the molecular mechanism responsible for p21WAF1 induction by Tam, we performed a deletion analysis on the p21WAF1 promoter. The minimal region in the p21WAF1 promoter required for Tam-activated induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. Our results showed that transcription factor Sp1 and Sp3 bound to this GC-rich region and mutation of Sp1-binding sites dramatically attenuated Tam-induced p21WAF1 promoter activity. We also tried to elucidate the signaling pathway that mediated the activation of p21WAF1 by Tam. Inhibition of mitogen-activated protein kinase pathways did not block Tam-induced p21WAF1. Similarly, protein kinase C inhibitor calphostin C could not suppress Tam-induced p21WAF1. Conversely, pretreatment of a specific protein kinase A inhibitor H89 significantly attenuated the induction of p21WAF1 by Tam. Furthermore, PKA activators forskolin and dibutyryl-cAMP activated p21WAF1 promoter activity and increased p21WAF1 protein level in lung cancer cells. Taken together, these results demonstrate that Tam activates the p21WAF1 promoter via Sp1-binding sites and suggest that PKA may be involved in the induction of p21WAF1 by Tam in ER-negative lung cancer cells.

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Acknowledgements

We thank Dr Vogelstein for providing the WWP-luc plasmid and Dr XF Wang for providing deletion mutant constructs of p21WAF1 promoter. The work was supported by a grant NSC 89-2320-B-037-009 from National Science Council of Republic of China.

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Lee, TH., Chuang, LY. & Hung, WC. Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells. Oncogene 19, 3766–3773 (2000). https://doi.org/10.1038/sj.onc.1203715

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