Research Paper Volume 15, Issue 12 pp 5426—5444
Chaetocin exhibits anticancer effects in esophageal squamous cell carcinoma via activation of Hippo pathway
- 1 Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- 2 Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
- 3 School of Pharmacy, North Sichuan Medical College, Nanchong, China
- 4 Department of Pharmacy, Nanchong Traditional Chinese Medicine Hospital, Nanchong, China
- 5 Institute of Tissue Engineering and Stem Cells, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- 6 Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, China
Received: February 28, 2023 Accepted: May 27, 2023 Published: June 14, 2023
https://doi.org/10.18632/aging.204801How to Cite
Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Dysfunction of the Hippo pathway is common in esophageal squamous carcinoma (ESCC). Chaetocin, a small molecular compound isolated from the marine fungus, exhibits potent anticancer effects. However, the anticancer effects of chaetocin on ESCC and its potential relationship to Hippo pathway remain unclear. Here, we demonstrated that chaetocin dramatically inhibited the proliferation in ESCC cells by causing cycle arrest in the M phase and activating the caspase-dependent apoptosis signaling pathway in vitro, and we also found that chaetocin induced the accumulation cellular reactive oxygen species (ROS). The RNA-seq analysis indicated that the Hippo pathway is one of the most enriched pathways after chaetocin treatment. We further revealed that chaetocin triggered the activation of Hippo pathway in ESCC cells, which is characterized by elevated phosphorylation levels of almost all core proteins in Hippo pathway, such as MST1 (Thr183), MST2 (Thr180), MOB1 (Thr35), LAST1 (Thr1079 and Ser909) and YAP (Ser127), ultimately leading to decreased nuclear translocation of YAP. Moreover, the MST1/2 inhibitor XMU-MP-1 not only partially rescued the inhibitory effect chaetocin-induced proliferation, but also rescued the chaetocin-induced apoptosis in ESCC cells. Furthermore, in vivo results confirmed the antitumor effect of chaetocin and its relationship with Hippo pathway. Taken together, our study demonstrates that chaetocin exhibits anticancer effects in ESCC via activation of Hippo pathway. These results provide an important basis for further research of chaetocin as a potential candidate for ESCC treatment.
Abbreviations
ESCC: Esophageal Squamous Cell Carcinoma; ROS: reactive oxygen species; MST: Mammalian Sterile20-like Kinase; MOB: MOBKL1; LAST1: large tumor suppressor kinase 1; YAP: Yes-associated protein 1 (YAP1); SAV1: salvador homolog 1; EdU: 5-Ethynyl-2′-deoxyuridine; CDK: Cyclin-dependent kinase; KEGG: Kyoto Encyclopedia of Genes and Genomes.