XIAP is highly expressed in melanoma and is associated with chemotherapy resistance

Abstract

8008 Background: Chemoresistance is a major problem in treating melanoma. The X-linked inhibitor of apoptosis (XIAP) is associated with chemoresistance in other cancers. Here we characterize XIAP expression in primary and metastatic melanomas and determine whether XIAP plays a role in chemoresistance. We report differential expression of XIAP between primary and metastatic melanomas and benign nevi. We demonstrate that inhibition of XIAP expression by Phenoxodiol can reverse chemoresistance. Methods: We employed tissue microarrays containing specimens from 548 melanoma patients and 540 benign nevi. XIAP expression was evaluated by an automated method for in situ quantitative analysis of protein levels (AQUA). We use S100 to define pixels as melanoma (tumor mask) within the array spot, and measure intensity of XIAP expression using Cy5 conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathological variables. Cell viability after exposure to Carboplatin and Phenoxodiol was determined in 3 melanoma cell strains using the CellTiter 96 Assay. Apoptosis was measured using the Caspase-3/7 GloTM Assay, and levels of XIAP and Caspase 2 were assessed by Western blots. Results: XIAP expression was significantly higher in melanomas than in nevi (P<0.0001), and higher in metastatic than in primary specimens (P<0.0001). All three melanoma cell strains examined were highly resistant to Carboplatin, and moderately resistant to Phenoxodiol. Pre-treatment with Phenoxodiol prior to Carboplatin induced a significant decrease in XIAP expression, which correlated with remarkable sensitization to Carboplatin. Conclusions: XIAP expression is higher in malignant melanocytes than in their benign counterparts. Expression is higher in early stage disease specimens than in metastatic specimens, suggesting an association with disease aggression. Phenoxodiol is a well tolerated drug, and has been shown to inhibit XIAP expression in ovarian cancer. Here we demonstrate that melanoma is resistant to Carboplatin, possibly due to XIAP expression. In vitro inhibition of XIAP by Phenoxodiol sensitizes melanoma cells to Carboplatin. This drug combination warrants further investigation as a therapeutic approach for metastatic melanoma. [Table: see text]