Abstract LB-038: Caspase-mediated iASPP cleavage inhibits NF-kB

Abstract Constitutive activation of the transcription factor nuclear factor-kB (NF-κB) plays an important role in oncogenesis and drug resistance of several types of human cancers. Inhibiting NF-κB pathways is therefore emerging as a promising approach to treat cancer. iASPP was first reported as an NF-κB binding partner and inhibitor in a yeast-two-hybrid system. However, it remains unknown how this activity is regulated in cells. For the first time, we show that the activity of iASPP is regulated by caspase-dependent cleavage at cellular level. iASPP was cleaved by caspases at a very early stage of treatment. Interestingly, in contrast to full-length iASPP that is predominantly cytosolic, the iASPP fragment accumulates in the nucleus. Cleaved iASPP shows increased interaction with NF-kB, which correlates with reduced activity of κB reporter. Overexpression iASPP fragment results in increased apoptosis. It also sensitizes cancer cells’ response to paclitaxe. Thus, this study reveals a novel mechanism by which caspase cleavage relocates iASPP from cytoplasm to the nuclear compartment and to pro-apoptotic machinery by binding and subsequent inhibiting NF-κB. This study also provides insights into new strategies to conquer drug resistance of NF-kB constitutive activated malignancies. Citation Format: Ying Hu, Wenjie Ge, Xinwen Wang, Xin Lu. Caspase-mediated iASPP cleavage inhibits NF-kB. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-038. doi:10.1158/1538-7445.AM2015-LB-038