Abstract 1401: Low proteasome activity and cancer stemness in colorectal cancer

Abstract

Abstract Background and aims: Emerging evidence indicates that existence of cancer stem-like cells (CSCs) is one of the main reasons of treatment resistance. Recently, several reports have indicated that some CSCs would be characterized by low proteasome activity. Material and methods: We engineered human colorectal cancer (CRC) cells to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg supposed to be accumulated in CSCs as a result of low activity of the 26S proteasome. The feature of Gdeghigh cells (low proteasome activity cells; LPACs) were analyzed by sphere formation assay, surface marker analysis, reactive oxygen species (ROS) analysis and assessment of chemotherapy and radiation therapy sensitivity. In addition, we explored the mechanism of treatment resistance of LPACs by using microarray analysis and clinical samples. Results: LPACs of CRC cells had significant radioresistance and chemoresistance (5-FU and oxaliplatin). Cancer stemness of LPACs was confirmed by CSC marker, sphere formation assay, ROS activity analysis, cell cycle assay, and in vivo tumorigenicity examination. Microarray analysis identified EID3 (EP300 Interacting Inhibitor of Differentiation 3) as a key factor related to treatment resistance of LPACs. Functional analyses of EID3 and analysis using clinical samples confirmed the role of EID3 in LPACs. Conclusions: CRC with low proteasome activity had character of treatment resistance and capacity of stemness. EID3 was a key factor related to treatment resistance of LPACs, and might be a novel therapeutic target. Citation Format: Mamoru Uemura, Koji Munakata, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Low proteasome activity and cancer stemness in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1401. doi:10.1158/1538-7445.AM2015-1401