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Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor that contributes to tumor cell growth and survival and is often constitutively active in several types of cancers, which makes it an attractive target for cancer therapy. We identified 5,5'-(pentane-1,5'-diyl)bis(2-methyl-1,4-benzoquinone) (BPMB) as a new STAT3 inhibitor. BPMB inhibited the transcriptional activities of STAT3, despite its inability to reduce the phosphorylation and nuclear translocation of STAT3. BPMB selectively inhibited the proliferation of human breast cancer cell lines with constitutively activated STAT3. Furthermore, a gel retardation pattern was obtained by immunoblotting only when those STAT3-activated cell lines were treated with BPMB. The shifted bands could be immunoblotted with anti-STAT3 antibody but not with anti-STAT1/STAT5 antibody, and were stable under reducing conditions. The purified recombinant STAT3 protein treated with BPMB afforded a similar band shift pattern. Matrix-assisted laser desorption/ionization-mass spectrometry analysis of the component comprising the main shifted band suggested that the complex is a STAT3 homodimer crosslinked by BPMB through a Michael addition with Cys550 in the linker domain. Alanine replacement at this position resulted in reduction of the STAT3 dimer formation in the gel retardation assay. Thus, our results suggest that BPMB inhibits the proliferation of STAT3-activated cell lines, presumably through acylation of the linker domain and subsequent induction of the inactive STAT3 complexes.

Discovery of a New STAT3 Inhibitor Acting on the Linker Domain