Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis
Article first published online: 25 JAN 2011
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Biochemistry
Volume 112, Issue 2, pages 463–475, February 2011
How to Cite
Ivanov, V. N., Partridge, M. A., Huang, S. X.L. and Hei, T. K. (2011), Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis. J. Cell. Biochem., 112: 463–475. doi: 10.1002/jcb.22934
- Issue published online: 25 JAN 2011
- Article first published online: 25 JAN 2011
- Accepted manuscript online: 15 NOV 2010 12:00AM EST
- Manuscript Accepted: 19 OCT 2010
- Manuscript Received: 7 JUL 2010
- Superfund. Grant Number: ES 10349
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.