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Targeting canonical and non-canonical STAT3 signaling by WB737, a novel potent STAT3 inhibitor, in natural killer/T-cell lymphoma

ABSTRACT: Activating mutations of STAT3 were frequently found in patients with natural killer/T-cell lymphoma (NKTL), suggesting that targeted inhibition of STAT3 is a potential therapeutic option for NKTL patients. Here, we have developed a novel and potent STAT3 inhibitor WB737 that directly binds to the STAT3-SH2 domain with high affinity. WB737 selectively inhibits cell growth of NKTL harbored STAT3 mutations through inducing apoptosis and blocking colony formation. Mechanistically, WB737 inhibits both canonical and non-canonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727 sites, respectively. Moreover, the activity of WB737 has a more potent inhibition on STAT3 compared to Sttatic, resulting in a significant anti-tumor effect followed by almost complete tumor regression in a NKTL xenograft model harboring STAT3 activating mutation. Collectively, these findings provide a preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202944 | GEO | 2023/06/21

REPOSITORIES: GEO

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Project description:Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC) and BarrettM-bM-^@M-^Ys adenocarcinomas (BAC) revealed similar STAT3 expression in ESCCs and BACs, but preferentially activated P-STAT3 in ESCCs. In vitro, strong STAT3 activation was seen by EGF-stimulation in OE21 (ESCC) cells, whilst OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 and OE33 cells and reduced cell migration in OE33, but not in OE21 cells. Transcriptome analysis identified STAT3-knockdown associated down-regulation of cell cycle processes and the selective down-regulation of cyclins and cyclin dependent kinaes associated genes in both OE21 and OE33 cells. Moreover, the transcriptome response showed changes in cell migration/invasion related genes that correlated with the associated phenotype measurements. This study demonstrates the importance of STAT3 expression and activation in esophageal carcinomas, whereby the extent differs between ESCCs and BACs. STAT3 knockdown significantly reduces cell proliferation in both types of esophageal cancer cells and inhibits migration in BAC cells. Thus, STAT3 may be further exploited as potential novel therapeutic target for esophageal cancers. The effect of STAT3 knock-down in OE33 and OE21 cells was calculated from three biologically independent experiments. 3x10e4 cells were seeded in triplicate in 24 well-plates and were transfected with twice 100nM STAT3 siRNA (pool of 4 STAT3 sequences, siGENOMEM-BM-.SMARTpoolM-BM-., Dharmacon RNAi Technologies, Thermo Fisher Scientific, Lafayette, USA) or SilencerM-BM-. negative siRNA control (Invitrogen/Life Technologies GmbH, Darmstadt, Germany) using 1M-BM-5l DharmaFECT (Dharmacon RNAi Technologies, Thermo Fisher Scientific, Lafayette, USA) transfection reagent for OE33 cells or siPORTTM NeoFXTM (Invitrogen/Life Technologies GmbH, Darmstadt, Germany) transfection reagent for OE21 cells. Differential gene regulation was quantified 72 hours after the first transfection by comparing separately for the OE21 and OE33 cells the STAT3 siRNA replicates and the respective cell lines containing the scrambled siRNA vector.

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Targeting canonical and non-canonical STAT3 signaling by WB737, a novel potent STAT3 inhibitor, in natural killer/T-cell lymphoma

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