Abstract 3883: Thyroid cancer cells with low proteasome activity have therapeutic resistance

Abstract

Abstract Background Thyroid cancer is the most frequent endocrine malignancy with a global increasing incidence. Papillary, follicular, and anaplastic thyroid carcinomas arise from endodermal-derived follicular cells, which represent the most abundant cellular population of the thyroid gland. The recent discovery of cancer stem cells (CSCs) in a variety of tumors has changed the view of carcinogenesis and therapeutic resistance. Therefore, the identification of CSCs in thyroid cancer represents a crucial step to elucidate the mechanism of therapeutic resistance, and develop effective therapies. It was previously reported that low intrinsic proteasome activity in glioma, pancreas, prostate, and breast cancer cells correlated with therapeutic resistance and CSCs properties. We hypothesized that a therapeutic resistant cell population with intrinsically low 26S proteasome activity can also be found in thyroid cancer. Materials and Methods We engineered human thyroid cancer cell lines (TPC-1, FRO, and WRO) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase from a retroviral vector. The green fluorescence accumulates in a small population of these cells as a result of low activity of the 26S proteasome. Result We identified a small population of cells with intrinsically low 26S proteasome activity in all thyroid cell lines. These populations have cisplatin, 5-FU, and radio-resistance. To further investigate differences between thyroid cancer cells with high and low proteasome activity, we studied their self-renewal capacity and tumorigenicity using an in vitro sphere-forming assay and an in vivo xenograft transplantation assay. Conclusion We conclude that established thyroid cancer cell lines are heterogeneous with regard to their intrinsic proteasome activity and that they contain a therapeutic resistant subpopulation of cells that can be identified by low proteasome activity. Further studies are needed to elucidate the mechanism that thyroid cancer cells with low proteasome activity have these properties. Learning Objective We identified thyroid cancer cells with low proteasome activity have therapeutic resistance and CSCs properties. Citation Format: Takahito Fukusumi, Hideshi Ishii, Masamitsu Konno, Shimpei Nishikawa, Yoshihiro Kano, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Kozo Noguchi, Masaaki Miyo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hidenori Inohara. Thyroid cancer cells with low proteasome activity have therapeutic resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2014-3883