TY - JOUR
T1 - Benzaldehyde suppresses epithelial-mesenchymal plasticity and overcomes treatment resistance in cancer by targeting the interaction of 14-3-3ζ with H3S28ph
AU - Saito, Jun
AU - Onishi, Nobuyuki
AU - Yamasaki, Juntaro
AU - Koike, Naoyoshi
AU - Hata, Yukie
AU - Kimura, Kiyomi
AU - Otsuki, Yuji
AU - Nobusue, Hiroyuki
AU - Sampetrean, Oltea
AU - Shimizu, Takatsune
AU - Okazaki, Shogo
AU - Sugihara, Eiji
AU - Saya, Hideyuki
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/7/27
Y1 - 2025/7/27
N2 - 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 14-3-3ζ 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. (Figure presented.)
AB - 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 14-3-3ζ 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. (Figure presented.)
UR - https://www.scopus.com/pages/publications/105004009195
UR - https://www.scopus.com/inward/citedby.url?scp=105004009195&partnerID=8YFLogxK
U2 - 10.1038/s41416-025-03006-4
DO - 10.1038/s41416-025-03006-4
M3 - Article
C2 - 40316727
AN - SCOPUS:105004009195
SN - 0007-0920
VL - 133
SP - 27
EP - 39
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 1
ER -
