Gene signature-guided isolation identifies cucurbitacins as STAT3 inhibitors from Picria fel-terrae Lour

Background

The transcription activator factor signal transducer and activator of transcription 3 (STAT3) diseases, such as triple-negative breast cancer (TNBC), making the need to identify new inhibitors crucial for effective treatment. In this regard, plants used in traditional Chinese medicine, including Picria fel-terrae Lour. (PFL), represent a rich source of bioactive compounds for identifying STAT3 inhibitors.

Aim

To identify novel STAT3 inhibitors in PFL based on a gene signature-guided isolation approach

Methods

Based on transcriptome analysis, we identified PFL as a potential source of STAT3 inhibitors. We used STAT3 downstream genes C-X-C motif chemokine ligand 10 and 11 (CXCL10 and CXCL11) to define the gene signature, and using qPCR, chemical isolation, and other selected methods, we validated STAT3 inhibitors, which were further assessed using TNBC animal models.

Results

By performing gene signature-guided isolation, we identified a number of candidate STAT3 inhibitors, namely, Cucurbitacin D (CuD), Cucurbitacin F (CuF), Cucurbitacin I (CuI), along with the novel compound, FN135422. Analyses of these compounds revealed that they inhibited phosphorylation of the Tyr705 residue of the STAT3 protein, and thus the transcriptional function of STAT3. Biochemical assays revealed that CuD, CuF, and CuI can bind directly to STAT3, and we identified one α,β-unsaturated carbonyl group as the important functional group of cucurbitacins associated with the inhibition of STAT3 function. Moreover, we demonstrated that these cucurbitacins can inhibit STAT3 function and TNBC growth in vivo.

Conclusion

With this study, we establish a novel approach for the isolation of function-specific bioactive compounds from the medicinal plant PFL, and identified cucurbitacins as potential STAT3-targeting antitumour agents.