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PPAR Research
Volume 2010, Article ID 729876, 8 pages
http://dx.doi.org/10.1155/2010/729876
Research Article

Combination PPAR and RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2

1Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
2University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO 80045, USA
3Department of Molecular Oncology, Ligand Pharmaceuticals, San Diego, CA 92121, USA

Received 11 May 2009; Accepted 28 July 2009

Academic Editor: Dipak Panigrahy

Copyright © 2010 Joshua P. Klopper et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nuclear hormone receptors, including RXR and PPAR , represent novel therapeutic targets in melanoma. We have previously shown that the DRO subline of the amelanotic melanoma A375 responds to rexinoid and thiazolidinedione (TZD) treatment in vitro and in vivo. We performed microarray analysis of A375(DRO) after TZD and combination rexinoid/TZD treatment in which the calcium binding protein S100A2 had increased expression after rexinoid or TZD treatment and a synergistic increase to combination treatment. Increased S100A2 expression is dependent on an intact PPAR receptor, but it is not sufficient to mediate the antiproliferative effects of rexinoid/TZD treatment. Over expression of S100A2 enhanced the effect of rexinoid and TZD treatment while inhibition of S100A2 expression attenuated the response to rexinoid/TZD treatment, suggesting that S100A2 is necessary for optimal response to RXR and PPAR activation by respective ligands. In summary, we have identified potential downstream mediators of rexinoid and TZD treatment in a poorly differentiated melanoma and found that alterations in S100A2 expression affect RXR and PPAR signaling in A375(DRO) cells. These studies provide insight into potential mechanisms of tumor response or resistance to these novel therapies.