Abstract 2244: AKT activation by Pdcd4 knockdown upregulates cyclin D1 expression and promotes cell proliferation
Authors: Wang Qing , Guo Xiaoling , Li Wenjuan , Yang Hsin-Sheng 
Published: August 2012

Programmed Cell Death 4 (Pdcd4) is a novel tumor suppressor that frequently exhibits down-regulated expression in several types of cancer. In colon cancer tissues, expression level of Pdcd4 is continuously down-regulated in the order of normal-adenoma-carcinoma. Over-expression of Pdcd4 has been demonstrated to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation and tumor phenotype. In addition to cultured cells, Pdcd4 transgenic mice that over-express Pdcd4 in the epidermis show significant reductions in 7,12-dimethylbenz(a)anthracene (DMBA)/TPA induced skin papilloma formation and carcinoma incidence. Knock-out of Pdcd4 expression in mice results in induction of lymphomas with frequent metastases to the liver and kidney, and an increase in DMBA/TPA induced skin papilloma formation and carcinoma incidence. These findings suggest that Pdcd4 suppresses carcinogenesis not only at an early stage (tumor promotion), but also at a late stage (tumor progression) in both cultured cells and transgenic mice. Recently, we showed that aerosol delivery of pdcd4 cDNA into a murine lung inhibits cell proliferation and enhances apoptosis in K-ras null mice and AP-1 reporter mice. Moreover, immunohistochemical studies showed that expression of Pdcd4 is inversely correlated with the proliferation marker, Ki-76, in the human tissues of intraductal papillary mucinous carcinoma. However, the mechanisms involved in these processes remain unknown. In this study, we found that knockdown of Pdcd4 promoted cell proliferation and up-regulated cyclin D1 expression. Previously, we demonstrated that Pdcd4 knockdown activated NF-κB dependent transcription. Mutations of NF-κB binding sites on the cyclin D1 promoter attenuated the cyclin D1 promoter activity induced by Pdcd4 knockdown. In addition, knockdown of NF-κB/IαB kinase (IKK) ≤ or IKKα, the kinase regulating NF-κB activation, inhibited cyclin D1 promoter activity and cyclin D1 expression, indicating that up-regulation of cyclin D1 by Pdcd4 knockdown is contributed, at least in part, by NF-κB activation. To investigate the mechanism of how Pdcd4 knockdown activates NF-κB, we found that the level of AKT phosphorylation and AKT kinase activity were increased in the Pdcd4 knockdown cells. Conversely, ectopic expression of Pdcd4 inhibited AKT phosphorylation and cyclin D1 expression, suggesting that Pdcd4 regulates AKT activity and cyclin D1 expression. Furthermore, knockdown of AKT in the Pdcd4 knockdown cells inhibited IKK phosphorylation, NF-κB activation, cyclin D1 promoter activity, and cyclin D1 expression as well as cell proliferation. Taken together, these findings suggest that activation of NF-κB by Pdcd4 knockdown through AKT contributes to the elevated cyclin D1 expression, thus provide new insights into how loss of Pdcd4 expression promotes tumor development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2244. doi:1538-7445.AM2012-2244