Benzaldehyde suppresses epithelial-mesenchymal plasticity and overcomes treatment resistance in cancer by targeting the interaction of 14-3-3ζ with H3S28ph
Menée à l'aide de lignées cellulaires et d'un modèle de greffe orthotopique de cancer du pancréas sur un modèle murin, cette étude met en évidence un mécanisme par lequel le benzaldéhyde supprime la plasticité épithélio-mésenchymateuse et lève la résistance des cellules cancéreuses à l'osimertinib ou aux rayonnements ionisants en ciblant l'interaction entre les protéines 14-3-3 zêta et la forme phosphorylée de l'histone H3 (H3S28ph)
Background : Benzaldehyde (BA) is an aromatic aldehyde found in fruits that has been studied as a potential anticancer agent on the basis of its ability to inhibit transformation in mouse embryo cells and to suppress metastasis in mice.
Methods : We investigated the cytotoxic effects of BA on cancer cells, and probed its effects on intracellular signaling pathways. The anticancer effects of BA in vivo were studied by using a mouse orthotopic transplantation model of pancreatic cancer.
Results : BA inhibited the growth of osimertinib- or radiation-resistant cancer cells as well as the interaction between 14-3-3
ζ and its client proteins. The interaction of 14-3-3ζ with the Ser28-phosphorylated form of histone H3 (H3S28ph) was implicated in treatment resistance and the transcriptional regulation of genes related to epithelial-mesenchymal transition and stemness, including E2F2, SRSF1, and ID1. Treatment of mice with a BA derivative inhibited pancreatic tumor growth and lung metastasis, as well as suppressed a state of epithelial-mesenchymal plasticity (EMP) of tumor cells.
Conclusion
:
The interaction between 14-3-3ζ and H3S28ph plays a key role in EMP and treatment resistance in cancer. The ability of BA to inhibit this and other interactions of 14-3-3ζ offers the potential to overcome treatment resistance and to suppress metastasis.
British Journal of Cancer , article en libre accès, 2025