Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis

Abstract

Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many Bleukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells.

Cucurbitacin I inhibits cell migration and invasion and enhances chemosensitivity in colon cancer

“…Previous reports have shown that cucurbitacin I suppresses STAT3 activation in other cancer cell lines, such as breast cancer (24) and leukemia cells (25). In the present study, we determined the effect of cucurbitacin I on STAT3 in colon cancer cells.…”

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

“…Nevertheless, among natural inhibitors, curcumin was shown to inhibit phosphorylation of STAT3 at both tyr705 and ser727 residues in biliary cancer cells (Prakobwong et al 2011). Interestingly, the inhibition of ser727 phosphorylation has been shown to induce apoptosis in Human B-leukemia and other cell lines constitutively expressing phosphorylated STAT3 in ser727 by curcubitacin-I (JSI-124) (Ishdorj et al 2010). Obviously, B-leukemia cells are known to express activated STAT3 with constitutive phosphorylation in ser727 but not in tyr705, supporting the role of ser727 phosphorylation in the oncogenic activity of STAT3 and suggesting this residue as a potential target for natural inhibitors of STAT3 activity.…”

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

“…[43][44][45][46][47] Several lines of evidence have indicated that cucurbitacin-I promotes cell cycle arrest and/or apoptosis in glioma, 48,49 lung, 42,50 breast, 51 and other malignancies. [52][53][54][55] Previously we observed that blockade of the JAK/STAT pathway by cucurbitacin-I enhanced the efficacy of SRC family kinase (SFK) inhibition with dasatinib in glioma cells. 48 Chumbalkar et al performed a tyrosine-directed search for signaling events downstream of DEGFR (EGFRviii) and identified STAT5 phosphorylation at Y699 as a key event.…”