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Cysteine (C)-X-C Receptor 4 Regulates NADPH Oxidase-2 During Oxidative Stress in Prostate Cancer Cells

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Cancer Microenvironment

Abstract

Reactive oxygen species (ROS) are implicated in many human diseases, including cancer. We have previously demonstrated that ROS increased the expression and activity of the chemokine receptor, CXCR4, which enhanced metastatic functions in prostate cancer cells. Studies have also revealed that CXCR4 and its ligand, SDF-1α, promoted ROS accumulation; however the source of ROS was not investigated. Recent evidence suggested that ROS accumulation in prostate cancer cell lines was contributed by the NADPH oxidase (NOX) family of enzymes. Herein, we sought to determine whether the CXCR4/SDF-1α signaling axis mediates ROS production through NOX in prostate cancer. We observed an increase in intracellular ROS generation in prostate cancer cells upon SDF-1α stimulation compared to untreated samples. Conversely, lower levels of ROS were detected in cells treated with AMD3100 (CXCR4 antagonist) or the ROS scavenger, N-acetyl-cysteine (NAC). Markedly reduced levels of ROS were observed in cells treated with apocynin (NOX inhibitor) compared to rotenone (mitochondrial complex I inhibitor)-treated cells. Specifically, we determined that NOX2 responded to, and was regulated by, the SDF-1α/CXCR4 signaling axis. Moreover, chemical inhibition of the ERK1/2 and PI3K pathways revealed that PI3K/AKT signaling participated in CXCR4-mediated NOX activity, and that these collective signaling events resulted in enhanced cell movement towards a chemoattractant. Finally, NOX2 may be a potential therapeutic target, as Oncomine microarray database analysis of normal prostate, benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN) tissue samples determined a correlation between NOX2 expression and prostate cancer. Taken together, these results suggest that CXCR4/SDF-1α-mediated ROS production through NOX2 enzymes may be an emerging concept by which chemokine signaling progresses tumorigenesis.

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Acknowledgments

We thank Dr. Jaideep Chaudhary for assistance in database mining. We also thank Dr. Ritu Aneja, Dr. Ayesha Don-Salu-Hewage and Vanessa L. Adams for technical assistance.

Grant Support

Research in this laboratory is supported, in part, by National Institutes of Health grants 2R25GM060414 (KJJ and ASDSH), P201MD002285 (CVH and VLA), F31CA153908 (MAC), and 8G12MD007590 (CVH), the American Association for the Advancement of Science (AAAS) Women’s International Research Collaborations (WIRC) for Minority Serving Institutions (MSIs), a National Science Foundation grant, and the United Negro College Fund-Henry C. McBay Fellowship.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr. S.W., Atlanta, GA, 30314, USA

    Kia J. Jones, Mahandranauth A. Chetram, Danaya A. Bethea, Latoya K. Bryant, Valerie Odero-Marah & Cimona V. Hinton

  2. Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, 30314, USA

    Kia J. Jones

  3. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA

    Mahandranauth A. Chetram

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  1. Kia J. Jones
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Correspondence to Cimona V. Hinton.

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Jones, K.J., Chetram, M.A., Bethea, D.A. et al. Cysteine (C)-X-C Receptor 4 Regulates NADPH Oxidase-2 During Oxidative Stress in Prostate Cancer Cells. Cancer Microenvironment 6, 277–288 (2013). https://doi.org/10.1007/s12307-013-0136-0

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