Abstract
Abstract Background. Recent evidence suggests that astrocytes protect cancer cells from chemotherapy by stimulating the upregulation of anti-apoptotic genes in cancer cells. We investigated the possibility that activation of the endothelin axis orchestrates survival gene expression and chemoprotection in MDA-MB-231 breast cancer cells and H226 lung cancer cells. Methods. Cancer cells, murine astrocytes, and murine fibroblasts were cultured in isolation and expression of endothelin (ET) peptides and ET receptors (ETAR and ETBR) was compared with expression on cancer cells and astrocytes (or cancer cells and fibroblasts) that were co-incubated for 48 hours. Type-specific endothelin receptor antagonists were used to evaluate the contribution of ETAR and ETBR to astrocyte-induced activation of the protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) signal transduction pathways, anti-apoptotic gene expression, and chemoprotection of cancer cells. We also investigated the chemoprotective potential of brain endothelial cells and microglial cells. Results. Gap junction signaling between astrocytes and MDA-MB-231 cancer cells stimulates upregulation of interleukin 6 (IL-6) and IL-8 expression in cancer cells, which increases ET-1 production from astrocytes and ET receptor expression on cancer cells. ET-1 signals for activation of AKT/MAPK and upregulation of survival proteins that protect cancer cells from taxol. Brain endothelial cell-mediated chemoprotection of cancer cells also involves endothelin signaling. Dual antagonism of ETAR and ETBR is required to abolish astrocyte- and endothelial cell-mediated chemoprotection. Conclusions. Bidirectional signaling between astrocytes and cancer cells involves upregulation and activation of the endothelin axis, which protects cancer cells from cytotoxicity induced by chemotherapeutic drugs. Citation Format: Mark S. Kim, Hyun Jin Choi, Ho-Jeong Lee, Junqin He, Qiuyu We, Robert R. Langley, Sin-Jin Kim, Isaiah J. Fidler. Role of the endothelin axis in astrocyte and endothelial cell mediated chemoprotection of cancer cells. [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 5463. doi:10.1158/1538-7445.AM2015-5463
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