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

• 발행기관: 대한생리학회-대한약리학회
• 저자명: Ruo Yu Meng Cong Shan Li Dan Hu Soon-Gu Kwon Hua Jin Ok Hee Chai Ju-Seog Lee Soo Mi Kim
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제27권 제5호, 493~511쪽, 전체 19쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2023.09.30

영문 초록

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 esopha-geal 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 esopha-geal 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 sup-pression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppres-sor 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 treat-ment 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, im-plying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

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키워드

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