Abstract 228: Cucurbitacin-I (JSI-124) induces apoptosis in chronic lymphocytic leukemia (CLL) cells through inhibiting STAT3 activation and XIAP expression

Abstract

Abstract Abstract AACR April-2010 Cucurbitacin-I (JSI-124) induces apoptosis in Chronic Lymphocytic Leukemia (CLL) cells through inhibiting STAT3 activation and XIAP expression. Ganchimeg Ishdorj, James B Johnston and Spencer B Gibson Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in North America. Current therapies control the disease but eventually the disease recurs and becomes drug resistant. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in cell survival and induces proliferation, whereas deletion of STAT3 results in cell death. Constitutive phosphorylation of STAT3 on tyrosine 705 residues has been found in a number of solid tumors and hematologic malignancies. Unlike other tumors, STAT3 is constitutively phosphorylated (p) on serine 727 but not on tyrosine residues in CLL. These observations lead to investigation of the effect of STAT3/JAK2 inhibitor Cucurbitacin-I (JSI-124) in CLL cells. We proposed that the targeting STAT3 phosphorylation may induce apoptosis in CLL cells. We studied B-cell lines (BJAB, I-83, NALM-6) and primary B-cells from patients with CLL using immunoprecipitation and found that JSI-124 suppressed serine pSTAT3 and induced apoptosis of these cells as determined by FACS analysis and membrane permeability assay. Using western blotting analysis, caspase-8 activation was observed in these cells after JSI-124 treatment. Since the activation of caspases are inhibited by members of the inhibitor of apoptosis (IAP) and Bcl-2 protein families and STAT3 has been shown to regulate their expression, we investigated anti-apoptotic members of these families. JSI-124 treatment led to downregulation of IAP protein XIAP, while Bcl-xL and Mcl-1 levels remained unchanged. In addition, JSI-124 selectively induced activation of JNK signaling pathways in CLL cells. Taken together, our results indicate that JSI-124 causes apoptosis through alterations in signal transduction pathways and could be a useful treatment in CLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 228.