Abstract 2190: cIAP2 as a therapeutic target in malignancies.

Abstract

Abstract [Introduction] Inhibition of the apoptotic pathway is one of the factors that may be responsible for carcinogenesis and drug resistance, and the inhibitor of apoptosis protein (IAP) family is thought to prevent apoptosis through inhibition of caspases and pro-caspases and may affect anti-cancer drug sensitivity. [Purposes] The purpose of this study is to clarify the roles of cellular inhibitor of apoptosis 2 (cIAP2) gene, which is a member of IAP family, on apoptosis and 5-FU sensitivity in cancer cells. [Methods and Results] The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and further 21 types of colon cancer cell lines were compared. 50% inhibitory concentration (IC50) of 5-FU in DLD-1/FU was over 100 times higher than that in DLD-1. With the analysis of expression profiles among 23 genes, we found that cIAP2 gene was up-regulated in DLD-1/FU compared with DLD-1 and other cell lines with low IC50. Next, the role of the cIAP2 gene was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after 5-FU-based chemotherapy. [Conclusion] IAPs are reported to be abnormally regulated and expressed in the majority of human malignancies at elevated levels. Among them, cIAP2 should be a possible therapeutic target in malignancies, especially in colorectal cancer. Citation Format: Koh Miura, Hideaki Karasawa, Wataru Fujibuchi, Shinobu Ohnuma, Michiaki Unno. cIAP2 as a therapeutic target in malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2013-2190