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Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis

Authors

  • Vladimir N. Ivanov,

    Corresponding author
    1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032
    • Center for Radiological Research, Columbia University, VC11-236, 630 West 168th Street, New York, NY 10032.
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  • Michael A. Partridge,

    1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032
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  • Sarah X.L. Huang,

    1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032
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  • Tom K. Hei

    1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032
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Abstract

Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKβ–NF-κB and JAK2–STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas. J. Cell. Biochem. 112: 463–475, 2011. © 2010 Wiley-Liss, Inc.

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