The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Previously, we showed that ERK downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a is degraded via an MDM2-mediated ubiquitin-proteasome pathway. Forkhead O transcription factors (FOXOs) play a pivotal role in the regulation of a myriad of cellular functions including cell cycle arrest, cell death and protection from stress stimuli. Activation of cell survival pathways such as PI3K/AKT/IKK or RAS/MEK/ERK are known to influence expression and function of FOXOs. Perturbation of FOXOs function leads to deregulated cell proliferation and accumulation of DNA damage, resulting in diseases such as cancer. To further elucidate the clinical relevance of MEK/ERK/FOXO3a regulation, in this study we included AZD6244 (ARRY-142886), which is an orally active, potent, specific and ATP-uncompetitive MEK1/2 inhibitor in phase II clinical trials. We found that blocking ERK activity with AZD6244 enhances FOXO3a expression in various human cancer cell lines in vitro and also in human colon cancer cell xenografts in vivo. We showed that knocking down FOXO3a and Bim impairs AZD6244-induced growth suppression, whereas restoring activation of FOXO3a was essential for sensitizing the resistant human cancer cell to AZD6244-induced growth arrest and apoptosis. Thus, up-regulation of FOXO3a and BimEL plays an essential role in suppression of tumor growth in response to MEK1/2 inhibitor, AZD6244. In this study, we exploit the novel functions of FOXOs revealed in recent studies and further elucidate FOXOs as new therapeutic targets for clinical drugs, such as AZD6244, in a broad spectrum of cancers.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2742.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009