Abstract 4781: XIAP expression is associated with poor prognosis and is a promising therapeutic target for the treatment of papillary thyroid carcinoma

Abstract

Abstract The inhibitor of apoptosis protein (IAP) family member, X-linked Inhibitor of Apoptosis Protein (XIAP) is essential for cell survival in variety of cancers. However, the role of XIAP overexpression in papillary thyroid carcinoma (PTC) is not fully elucidated. Therefore, we analyzed the expression of XIAP protein and its clinico-pathological correlation in a large cohort of Middle Eastern PTC by immuno-histochemistry in a tissue micro-array format followed by in vitro studies using PTC cell lines. XIAP was found to be over-expressed in 25% of PTC and directly associated with older age (p<0.0001) and presence of extra-thyroidal extension (p<0.0001). Interestingly, XIAP was also found to be significantly associated with tall-cell variant (p=0.0013), larger tumor size (p=0.0002) and advanced stage (III and IV) disease (p< 0.0001). XIAP over-expression was also significantly associated with over-expression of oncogenic c-Met (p=0.0010) and anti-apoptotic Bcl-Xl protein (p<0.0001). Finally, PTC with XIAP over-expression showed a significantly poor disease free survival (p=0.0476) of 63.1 months as compared to the PTC's with low XIAP expression (74.0 months). Our in vitro data showed that embelin, a selective inhibitor of XIAP, caused a dose dependent inhibition of cell proliferation in PTC cell lines. Furthermore, we found that embelin induced a dose dependent apoptosis as detected by cell cycle analysis and annexin V/PI dual staining in PTC cells. On further analysis, our data showed that embelin induced a caspase-dependent apoptosis of PTC cells via activation and cleavage of capsases-9 and -3 and cleavage of PARP. In summary, our clinical data highlights the fact that XIAP over-expression in PTC confer a aggressive phenotype with poor outcome. In vitro studies using XIAP inhibitor suggest that this sub-group of PTC with over-expression of XIAP can be therapeutically targeted to induce efficient apoptosis in these cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4781. doi:10.1158/1538-7445.AM2011-4781