Abstract 3560: Bcl-Xl over-expression is a poor prognostic marker in papillary thyroid cancer and can be therapeutically targeted to induce apoptosis and autophagy

Abstract

Abstract Bcl-Xl is a member of the Bcl-2 family of proteins that are divided into either pro-apoptotic proteins or anti-apoptotic proteins on the basis of their functionality. All the members of the Bcl-2 family share common domains known as Bcl-2 Homology (BH1-4) domain. The pro-apoptotic family members include proteins that only contain the BH-3 domain and include Bax, Bak, Bid, PUMA, NOXA, Bim and Bad while the anti-apoptotic proteins include members such as Bcl-2, Bcl-Xl and Mcl-1. In normal conditions, there is a balance between the pro- and anti-apoptotic members of the Bcl-2 family. Because of their important role in cell survival, there has been lot of interest in utilizing dysregulation of Bcl-2 family members to counter cancer growth and induce apoptosis. Bcl-Xl is an anti-apoptotic protein that has found to be over-expressed in various cancers including lung cancer, DLBCL and breast cancer. However, the role of Bcl-Xl in papillary thyroid cancer (PTC) from Middle Eastern region has not been fully illustrated. In order to investigate the role of Bcl-Xl in PTC, we examined the expression of Bcl-Xl in a cohort of 1022 PTC clinical cases by immunohistochemistry in a tissue microarray format and found that Bcl-Xl was over-expressed in 51.7% of PTC cases. Bcl-Xl over-expression was significantly associated with aggressive high proliferative markers such as older age (p = 0.0009), extra-thyroidal extension (p<0.0001), tumor size (p = 0.0081), nodal involvement (p = 0.0067), metastasis (p = 0.0013) and showed a poor overall 5 year survival (0.0438). Bcl-Xl over-expression was was also found to be significantly associated with p-AKT (p<0.0001), XIAP (p<0.0001) and proliferative marker Ki67 (p = 0.0041). In vitro, targeting Bcl-Xl expression in PTC cell lines using a small molecular inhibitor of Bcl-Xl; AB141657 (Z36) showed a dose dependent inhibition of cell viability and induction of apoptosis after 48 hours treatment. Using 5 and 10μM Z36, we found that PTC cells not only underwent apoptosis detected by flow cytometry, inactivation of AKT and activation of mitochondrial apoptotic pathway but also autophagy as detected by up-regulation of LC1-3, inactivation of p-mTOR1 and p-mTOR2 and their downstream targets. These data clearly indicate a role of Bcl-Xl in the pathogenesis of PTC as well as the importance of targeting Bcl-Xl using Z36 to induce both; apoptosis and autophagy in Bcl-Xl over-expressing PTC cells. Citation Format: Azhar R. Hussain, Maqbool Ahmed, Shaham Beg, Rong Bu, Roxanne Melosantos, Zeeshan Qadri, Saif Al-Sobhi, Fouad Al-Dayel, Abdul Khalid Siraj, Khawla S. Al-Kuraya. Bcl-Xl over-expression is a poor prognostic marker in papillary thyroid cancer and can be therapeutically targeted to induce apoptosis and autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3560.