Regulation of Hippo–YAP signaling axis by Isoalantolactone suppresses tumor progression in cholangiocarcinoma

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Highlights

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Isoalantolactone (IALT) exhibits cytotoxic effects on aggressive cholangiocarcinoma (CCA) cells.
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IALT induces apoptosis and modulates Yes-associated protein (YAP) signaling in SNU478 cells.
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The study confirms the involvement of the Hippo pathway through LATS1/LATS2 knockout cells.
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IALT suppresses cell growth, migration, and influences YAP-TEAD activity in CCA.

Abstract

Cholangiocarcinoma (CCA) is a devastating malignancy characterized by aggressive tumor growth and limited treatment options. Dysregulation of the Hippo signaling pathway and its downstream effector, Yes-associated protein (YAP), has been implicated in CCA development and progression. In this study, we investigated the effects of Isoalantolactone (IALT) on CCA cells to elucidate its effect on YAP activity and its potential clinical significance. Our findings demonstrate that IALT exerts cytotoxic effects, induces apoptosis, and modulates YAP signaling in SNU478 cells. We further confirmed the involvement of the canonical Hippo pathway by generating LATS1/LATS2 knockout cells, highlighting the dependence of IALT-mediated apoptosis and YAP phosphorylation on the Hippo-LATS signaling axis. In addition, IALT suppressed cell growth and migration, partially dependent on YAP-TEAD activity. These results provide insights into the therapeutic potential of targeting YAP in CCA and provide a rationale for developing of YAP-targeted therapies for this challenging malignancy.

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Cancer statistics, 2023

Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Jesus Banales, Jose Marin, Angela Lamarca … (2020)

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

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Biliary tract cancer

Juan W. Valle, R Katie Kelley, Bruno Nervi … (2021)

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Author and article information

Contributors

Jung-Soon Mo

Han-Sol Jeong

Journal

Journal ID (nlm-ta): Transl Oncol

Journal ID (iso-abbrev): Transl Oncol

Title: Translational Oncology

Publisher: Neoplasia Press

ISSN (Electronic): 1936-5233

Publication date PMC-release: 25 May 2024

Publication date Collection: August 2024

Publication date (Electronic): 25 May 2024

Volume: 46

Electronic Location Identifier: 101971

Affiliations

[a ]Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon 16499, South Korea

[b ]Three-Dimensional Immune System Imaging Core Facility, Ajou University, Suwon 16499, South Korea

[c ]Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, South Korea

[d ]Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan 50612, South Korea

[e ]Department of Neurosurgery, Ajou University School of Medicine, Suwon 16499, South Korea

[f ]Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, South Korea

Author notes

[* ]Corresponding author at: Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, South Korea. j5mo@ 123456ajou.ac.kr

[** ]Corresponding author. jhsol33@ 123456pusan.ac.kr

[1]

These authors contributed equally to this work.

Article

Publisher Item ID: S1936-5233(24)00098-6 Publisher ID: 101971

DOI: 10.1016/j.tranon.2024.101971

PMC ID: 11152753

PubMed ID: 38797019

SO-VID: a705285e-6852-41d0-a996-dd9c519209a1

License:

This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

History

Date received : 18 January 2024

Date revision received : 12 April 2024

Date accepted : 17 April 2024

Regulation of Hippo–YAP signaling axis by Isoalantolactone suppresses tumor progression in cholangiocarcinoma

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Neuronal Signaling

Most cited references 53

Cancer statistics, 2023

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Biliary tract cancer

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