Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

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Abstract

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family ( RASSF1), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

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Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu … (2012)

The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.

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Hippo signaling: growth control and beyond.

Georg Halder, Randy L. Johnson (2011)

The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.

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The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration

Todd Heallen, Jun Wang, Shijie Liu … (2018)

The Hippo-YAP (Yes-associated protein) pathway is an evolutionarily and functionally conserved regulator of organ size and growth with crucial roles in cell proliferation, apoptosis, and differentiation. This pathway has great potential for therapeutic manipulation in different disease states and to promote organ regeneration. In this Review, we summarize findings from the past decade revealing the function and regulation of the Hippo-YAP pathway in cardiac development, growth, homeostasis, disease, and regeneration. In particular, we highlight the roles of the Hippo-YAP pathway in endogenous heart muscle renewal, including the pivotal role of the Hippo-YAP pathway in regulating cardiomyocyte proliferation and differentiation, stress response, and mechanical signalling. The human heart lacks the capacity to self-repair; therefore, the loss of cardiomyocytes after injury such as myocardial infarction can result in heart failure and death. Despite substantial advances in the treatment of heart failure, an enormous unmet clinical need exists for alternative treatment options. Targeting the Hippo-YAP pathway has tremendous potential for developing therapeutic strategies for cardiac repair and regeneration for currently intractable cardiovascular diseases such as heart failure. The lessons learned from cardiac repair and regeneration studies will also bring new insights into the regeneration of other tissues with limited regenerative capacity.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 23 September 2019

Publication date Collection: October 2019

Volume: 20

Issue: 19

Electronic Location Identifier: 4709

Affiliations

[1 ]Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 54907, Korea; shkimgi@ 123456jbnu.ac.kr

[2 ]Department of Physiology, Chonbuk National University Medical School, Jeonju 54907, Korea; jinhuaxy@ 123456126.com (H.J.); kathymeng1216@ 123456gmail.com (R.Y.M.); kdyeah@ 123456jbnu.ac.kr (D.-Y.K.); liu_yuchuan@ 123456126.com (Y.C.L.)

[3 ]Department of Anatomy and Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, Korea; okchai1004@ 123456jbnu.ac.kr

[4 ]Department of Biochemistry, Chonbuk National University Medical School, Jeonju 54907, Korea; bhpark@ 123456jbnu.ac.kr

[5 ]Research Institute of Clinical Medicine of Chonbuk National University, Jeonju 54907, Korea

[6 ]Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea

Author notes

[* ]Correspondence: soomikim@ 123456jbnu.ac.kr ; Tel.: +82-63-270-3077; Fax: +82-63-274-9892

[†]

These authors contributed equally to this work.

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Seong-Hun Kim https://orcid.org/0000-0002-7592-8060

Ok Hee Chai https://orcid.org/0000-0003-2889-9743

Article

Publisher ID: ijms-20-04709

DOI: 10.3390/ijms20194709

PMC ID: 6801984

PubMed ID: 31547587

SO-VID: 57d2032d-4703-488c-8108-5566a46dd2fb

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

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Most cited references 39

Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

Hippo signaling: growth control and beyond.

The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration

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