Abstract 4951: The role of endothelin axis signaling pathway in astrocyte mediated chemoprotection of tumor cells.

Abstract

Abstract Purpose: More than 40% of patients with the breast cancer develop brain metastasis that are resistant to conventional chemotherapeutic agents. We have reported that reactive astrocytes establish gap junction communication channels with adjacent tumor cells and protect tumor cells from chemotherapy by up-regulation of survival genes in the tumor cells. We now report on the mechanism by which astrocytes up-regulate expression of the survival genes in tumor cells. Materials and Methods: Human breast cancer cells, MDA-MB-231 cultured with murine astrocytes produce endothelin 1 (ET-1) leading to expression and activation of endothelin receptors (ETRs). Using small interfering RNA (siRNA) of ETAR and ETBR, and ETRs specific antagonists (BQ123, BQ788, and PD145065) demonstrated the correlation between the activation of the endothelin axis in tumor cells and the induction of survival genes (BCL2L1, GSTA5, and TWIST1) leading to chemoresistance. Results: Co-culture of MDA-MB-231 cells and murine astrocytes induced up-regulation of ETRs (ETAR and ETBR) and activation of endothelin receptors axis in tumor cells as well as increased production of ET-1 by murine astrocytes. Activation of the ETRs by exogenous ET-1 up-regulated the expression of survival genes, such as BCL2L1, GSTA5 and TWIST1 via activation of phosphorylated AKT/MAPKinase signal transduction pathways, leading to resistance of tumor cells to several chemotherapeutic agents. Knockdown of both ETAR and ETBR by siRNAs or treatment of tumor cells with dual ETR inhibitor abolished the chemoprotection induced by astrocytes. Conclusion: ET axis signaling pathway plays an essential role in astrocytes-mediated induction of chemoresistance of tumor cells by up-regulation of survival genes in tumor cells. Simultaneous blockade of both ETR can prevent tumor cells from developing resistance to chemotherapeutic agents. Citation Format: Seung Wook Kim, Sun Jin Kim, Hyun Jin Choi, Ho-Jeong Lee, Junqin He, Qiuyu Wu, Erica J. Lawson, Isaiah J. Fidler. The role of endothelin axis signaling pathway in astrocyte mediated chemoprotection of tumor 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 4951. doi:10.1158/1538-7445.AM2013-4951