title: A novel CXCR3-B chemokine receptor-induced growth-inhibitory signal in cancer cells is mediated through the regulation of Bach-1 protein and Nrf2 protein nuclear translocation.
abstract: Chemokines and their receptors play diverse roles in regulating cancer growth and progression. The receptor CXCR3 can have two splice variants with opposite functions. CXCR3-A promotes cell growth, whereas CXCR3-B mediates growth-inhibitory signals. However, the negative signals through CXCR3-B in cancer cells are not well characterized. In this study, we found that CXCR3-B-mediated signaling in MCF-7 and T47D breast cancer cells induced apoptotic cell death. Signals through CXCR3-B decreased the levels of the antiapoptotic proteins Bcl-2 and Bcl-xL and increased the expression of apoptotic cleaved poly(ADP-ribose) polymerase. Along with up-regulation in apoptosis, CXCR3-B signals were associated with a decrease in cellular autophagy with reduced levels of the autophagic markers Beclin-1 and LC3B. Notably, CXCR3-B down-regulated the expression of the cytoprotective and antiapoptotic molecule heme oxygenase-1 (HO-1) at the transcriptional level. There was an increased nuclear localization of Bach-1 and nuclear export of Nrf2, which are important negative and positive transcription factors, respectively, for HO-1 expression. We also observed that CXCR3-B promoted the activation of p38 MAPK and the inhibition of ERK-1/2. CXCR3-B could not induce cancer cell apoptosis at the optimal level when we either inhibited p38 activity or knocked down Bach-1. Further, CXCR3-B-induced apoptosis was down-regulated when we overexpressed HO-1. Together, our data suggest that CXCR3-B mediates a growth-inhibitory signal in breast cancer cells through the modulations of nuclear translocation of Bach-1 and Nrf2 and down-regulation of HO-1. We suggest that the induction of CXCR3-B-mediated signaling can serve as a novel therapeutic approach where the goal is to promote tumor cell apoptosis.
authors.affiliation: From the Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115 and.
authors.forename: Murugabaskar
authors.initials: M
authors.lastname: Balan
authors.forename: Soumitro
authors.initials: S
authors.lastname: Pal
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C102108:BACH1 protein, human; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D000071186:Beclin-1; C515187:CXCR3 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020033:Protein Isoforms; D054367:Receptors, CXCR3; D051020:bcl-X Protein; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Apoptosis; Chemokines; Heme Oxygenase; Nrf2; Nuclear Transport; Signal Transduction; Signaling