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.
Keywords:
Apoptosis; Chemokines; Heme Oxygenase; Nrf2; Nuclear Transport; Signal Transduction; Signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Alternative Splicing / genetics
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / metabolism*
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Beclin-1
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Cell Nucleus / pathology
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Fanconi Anemia Complementation Group Proteins / genetics
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Fanconi Anemia Complementation Group Proteins / metabolism*
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Female
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Heme Oxygenase-1 / biosynthesis
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Heme Oxygenase-1 / genetics
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Humans
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MAP Kinase Signaling System*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism*
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Receptors, CXCR3 / genetics
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Receptors, CXCR3 / metabolism*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Apoptosis Regulatory Proteins
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BACH1 protein, human
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BCL2L1 protein, human
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BECN1 protein, human
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Basic-Leucine Zipper Transcription Factors
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Beclin-1
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CXCR3 protein, human
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Fanconi Anemia Complementation Group Proteins
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MAP1LC3B protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Protein Isoforms
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Receptors, CXCR3
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bcl-X Protein
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HMOX1 protein, human
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Heme Oxygenase-1
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases