Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3′3-diindolylmethane suppresses esophageal cancer tumorigenesis

Ruo Yu Meng; Cong Shan Li; Dan Hu; Soon-Gu Kwon; Hua Jin; Ok Hee Chai; Ju-Seog Lee; Soo Mi Kim

doi:10.4196/kjpp.2023.27.5.493

Indexed in SCIE, Scopus, PubMed & PMC

pISSN 1226-4512 eISSN 2093-3827

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Korean J Physiol Pharmacol 2023; 27(5): 493-511

Published online September 1, 2023 https://doi.org/10.4196/kjpp.2023.27.5.493

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3′3-diindolylmethane suppresses esophageal cancer tumorigenesis

Ruo Yu Meng^1,#, Cong Shan Li^1,#, Dan Hu¹, Soon-Gu Kwon², Hua Jin³, Ok Hee Chai⁴, Ju-Seog Lee⁵, and Soo Mi Kim^1,*

¹Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, ²Department of Oral Physiology, School of Dentistry, Kyung Hee University, Seoul 02447, Korea, ³School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China, ⁴Department of Anatomy, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea, ⁵Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Correspondence to:Soo Mi Kim
E-mail: soomikim@jbnu.ac.kr

^#These authors contributed equally to this work.

Author contributions: R.Y.M. wrote the draft. C.S.L. and D.H. conducted in vitro and in vivo experiment. S.G.K. conducted biology study and H.J. performed formal analysis. O.H.C. conducted the histology study. J.S.L. conducted the statistical analysis. S.M.K. designed the experiment and described the paper. The final draft of the manuscript was reviewed and approved by all the authors.

Received: June 6, 2023; Revised: August 4, 2023; Accepted: August 10, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3′3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

Keywords: 3′,3-diindolylmethane, Akt, Esophageal squamous cancer cells, Hippo signaling pathway, Ursolic acid, YAP