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Cited by 86Cell death mechanisms and regulationCancer-related Molecular PathwaysProtein Kinase Regulation and GTPase Signaling

Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase

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Nakagawa, Hayato, Hirata, Yoshihiro, Takeda, Kohsuke, Hayakawa, Yoku, Sato, Takehiro, Kinoshita, Hiroto, Sakamoto, Kei, Nakata, Wachiko +6 more·2011·Hepatology
DOI 10.1002/hep.24357
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Abstract

The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1−/−) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1−/− mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1−/− HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1−/− HCCs. ASK1−/− mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1−/− mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway. Conclusion: ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis. (HEPATOLOGY 2011;)

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  • Gstm2 has been shown to increase liver tumorigenesis through inactivation of ASK1, a kinase that promotes apoptosis.

    “Gstm2 has been shown to increase liver tumorigenesis through the inactivation of ASK1, a kinase that promotes apoptosis (49, 50).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [50]

    The Discussion (page unavailable) concludes that ASK1 acts as a tumor suppressor in hepatocarcinogenesis, and the apoptosis results report fewer apoptotic tumor cells in ASK1-deficient mice. The paper supports the ASK1 portion of the claim, but searches for Gstm2 and its proposed inactivation of ASK1 found no passage supporting that mechanism. (LLM, conf=0.87)

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Cited by

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Authors
Nakagawa, H., Hirata, Y., Takeda, K., Hayakawa, Y., Sato, T., Kinoshita, H., Sakamoto, K., Nakata, W., Hikiba, Y., Omata, M., Yoshida, H., Koike, K., Ichijo, H., & Maeda, S.
Affiliations
  • The University of Tokyo (JP)
  • The Institute of Medical Science, Asahi Life Foundation (JP)
  • Yamanashi Prefectural Hospital Organization (JP)
Corresponding author
Maeda, Shin
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-07
Volume
54
Issue
1
Pages
185-195
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.24357
OpenAlex
W2170791797
Cited by
86
References
1
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 2 · 2013: 7 · 2012: 13
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1 (tdm, 1523 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (20229004, 23659033)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
ASK1, hepatocarcinogenesis, hepatocellular carcinoma, JNK, p38 MAPK, tumor suppressor, Fas-mediated apoptosis, death receptor signaling, DNA damage response, p21, diethylnitrosamine, adenoviral gene transfer, Bcl-2 family proteins
MeSH terms
Bcl-2-Like Protein 11, Animals, Diethylnitrosamine, Disease Models, Animal, Carcinoma, Hepatocellular, Liver Neoplasms, Male, Membrane Proteins, Proto-Oncogene Proteins, Stress, Physiological, Signal Transduction, Apoptosis, Mice, Knockout, Mitogen-Activated Protein Kinases, Hepatocytes, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, MAP Kinase Kinase Kinase 5, Cell Proliferation, Apoptosis Regulatory Proteins, Mice

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