title: Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells.
abstract: BACKGROUND
  Recent evidence suggests that astrocytes protect cancer cells from chemotherapy by stimulating upregulation of anti-apoptotic genes in those 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 grown in isolation, and expression of endothelin (ET) peptides and ET receptors (ETAR and ETBR) 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 MDA-MB-231 cancer cells and astrocytes 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.
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (S.W.K., H.J.C., H.-J.L., J.H., Q.W., R.R.L., I.J.F., S.-J.K.).
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016232:Endothelins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D017466:Receptors, Endothelin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin
keywords: astrocytes; brain metastasis; breast cancer; endothelin; therapeutic resistance