Abstract 4907: Upregulation of furin is associated with the invasiveness of cumulatively irradiated cancer cells

Abstract

Abstract Furin, a subtilisin/kesin-like proprotein convertase (PC), activates membrane-bound MT1-MMP, which facilitates pro-gelatinase A (MMP2). These activated MT1-MMP and MMP2 are involved in cancer cell invasion and metastasis. In this study, we investigate the contribution of MMP2 activated by furin to cellular invasiveness of cumulatively irradiated cells. Using previously established AMC-HN3 and AMC-HN8 cell line from laryngeal carcinoma patient, we have generated isogenic model of cumulatively irradiated AMC-HN3R and AMC-HN8R cell line, respectively. AMC-HN3R cells were increased furin expression with upregulation of MT1-MMP/MMP2 and their invasiveness by two fold (p < 0.05) compared to AMC-HN3, while AMC-HN8R cells had no differences compared to AMC-HN8. In case of AMC-HN3R, inhibition of furin activity with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethyl-keton, CMK, showed a significant decrease of MT1-MMP/MMP2 and in vitro cellular invasiveness. Tumors obtained after subcutaneous (s.c.) inoculation of AMC-HN3R cells were larger, developed earlier and increased more furin than the tumor of parent cells, AMC-HN3. Although AMC-HN3R and AMC-HN8R cells identically undergo EMT, inhibition of furin activity decreases activated MMP2 and invasive potential of HN3R cell line unlike HN8R cell line, suggesting that furin is a potentially useful target for therapeutics. Citation Format: Myungjin Lee, Changhwan Rhu, Seong Who Kim, Sang Yoon Kim. Upregulation of furin is associated with the invasiveness of cumulatively irradiated cancer cells. [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 4907. doi:10.1158/1538-7445.AM2014-4907