Abstract 2105: Advanced glycation end products of type I collagen promote cell proliferation and resistance against doxorubicin in HT-1080 cancer cells.

Abstract

Abstract Resistance to apoptosis and chemotherapy is a critical factor in cancer recurrence and patient relapse. Extracellular matrix via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy (Aoudjit and Vuori, Chemother Res Pract. 2012;2012:283181). However, the effects of extracellular matrix advanced glycation end products (AGE) on cell proliferation and sensitivity to chemotherapy is not well established. In this study, we investigated whether type I collagen and particularly its AGE are involved in cell proliferation and resistance to doxorubicin in human fibrosarcoma HT-1080 cancer cells. Type I collagen was extracted from rats tail tendons (10 days, 8 and 96 weeks-old) and prepared as already described (Millerot-Serrurot et al., 2010, Cancer Cell Int, 13: 10-26). First, we characterized the glycation pattern of the different collagens using SDS-PAGE electrophoresis and fluorescence spectroscopy. A significant increase in AGE level has been observed in collagen extracted from 8 and 96 weeks-old rats. AGE level was significantly higher in collagen extracted from 96 weeks-old rats when compared to 8 weeks-old ones. Only collagen extracted from 96 weeks-old rats was able to induce 3-fold increase in proliferation of HT-1080 cells. Western-blot analysis showed that activation of MAPK/ERK, but not PI3K/AKT, was required for collagen AGE mediated cell proliferation. The MAPK/ERK inhibitor U0126 abolished this effect. Both collagens were able to inhibit doxorubicin-induced apoptosis in HT-1080 cells. Moreover, protection against apoptosis was significantly higher in the presence of collagen extracted from 96 weeks-old rats. Our data suggest extracellular matrix AGE signalling as an important promoter of cancer cell proliferation and that this pathway may contribute to a new mechanism of drug resistance. Citation Format: Charles Saby, Hassan EL Btaouri, Laurence Van Gulick, Marie Guilbert, Pierre Jeannesson, Hamid Morjani. Advanced glycation end products of type I collagen promote cell proliferation and resistance against doxorubicin in HT-1080 cancer cells. [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 2105. doi:10.1158/1538-7445.AM2013-2105