Abstract
BackgroundTargeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells.ResultsFLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ.ConclusionOur findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.
Highlights
The Signal Transducer and Activator of Transcription 3 (STAT3) protein is a member of the STAT family of transcription factors which are initially located in the cytoplasm in their inactive form
FLLL32, a curcumin analog that is designed to target STAT3 Computer models with molecular docking showed that only the keto form of curcumin binds to the STAT3 Src-homology 2 (SH2) dimerization site (Table 1)
We found that pretreatment with FLLL32 but not curcumin (20 μM) was able to inhibit the induction of STAT3 phosphorylation by IL-6 in MDA-MB-453 breast cancer cells, and the effect of FLLL32 was more potent than curcumin (Figure 4A, B)
Summary
The Signal Transducer and Activator of Transcription 3 (STAT3) protein is a member of the STAT family of transcription factors which are initially located in the cytoplasm in their inactive form. Blocking constitutive STAT3 signaling in carcinoma cells by STAT3 antisense oligonucleotides, STAT3 small interfering RNAs (siRNAs), or stable transfection of dominant-negative STAT3 [5] can inhibit cancer cells growth, invasion and metastasis, and induce apoptosis. Inhibition of constitutive STAT3 signaling by the JAK2 inhibitor, AG490 [6] suppressed the growth, and decreased the invasion of human hepatocellular carcinoma cells, and induced apoptosis in multiple myeloma cells [7]. These findings suggest that constitutive STAT3 signaling is crucial to the survival, invasion, and growth of human carcinoma cells. A novel small molecular STAT3 inhibitor, FLLL32 was designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells
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