Cyclooxygenase-2 (COX-2) induction by epidermal growth factor (EGF) is likely to be an important response to this growth factor in gliomas given its prognostic significance in these tumors. Gaining a greater understanding of the signaling pathway(s) involved in this response may permit development of novel approaches for disrupting this induction with potential therapeutic benefit in such patients. Previously, we showed that p38-MAPK and protein kinase C-delta were required signal transducers in this process that ultimately leads to Sp1-dependent transcriptional activation of the COX-2 promoter in glioma cells. In this current work, we find that the FoxM1 transcription factor is also needed for full induction of COX-2 in response to EGF. Src kinase acts upstream of p38-MAPK to induce both FoxM1 and COX-2 expression. Furthermore, siRNA suppression of FoxM1 significantly reduces COX-2 induction in response to both EGF and the downstream signal transducers Src and p38-MAPK. In addition, increased expression of FoxM1 in an inducible system leads to increased COX-2 expression. Evaluation of the COX-2 promoter in a reporter gene system revealed that while FoxM1 overexpression can have a small effect on promoter activity through the FoxM1 consensus site at approximately -2.5k upstream of the promoter start site, its main activity appears to be through the Sp1 consensus site located from -245 to -240 upstream of the start site. Interestingly, FoxM1 associates with Sp1 by coimmunoprecipitation. In fact, FoxM1 can associate with the Sp1 consensus site both in vitro as assessed by electrophoretic mobility shift assay (EMSA) and in vivo as assessed by a chromatin immunoprecipitation (CHIP) assay. This work demonstrates a novel interaction between Sp1 and FoxM1 whereby FoxM1 can activate transcription of COX-2 through the associated Sp1 factor's consensus site.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2046. doi:10.1158/1538-7445.AM2011-2046