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Cited by 120Cytokine Signaling Pathways and InteractionsNatural product bioactivities and synthesisProtein Tyrosine Phosphatases

Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3

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Ahmad, Rehan, Raina, Deepak, Meyer, Colin, Kufe, Donald·2008·Cancer Research
DOI 10.1158/0008-5472.can-07-3036PMC PMC3092292
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Abstract

The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains α,β-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)–induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys1077 in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6–induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys259 and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1→STAT3 pathway by forming adducts with both JAK1 and STAT3. [Cancer Res 2008;68(8):2920–6]

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  • CDDO-Me inhibits constitutive and IL-6-induced JAK1 activity by directly binding to Cys1077 in the JAK1 kinase domain, blocking phosphorylation of STAT3 at Y705.

    “CDDO-Me inhibits constitutive and IL-6–induced JAK1 activity by directly binding to Cys1077 in the JAK1 kinase domain, thereby blocking its ability to phosphorylate STAT3 at Y705.”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Ahmad et al., 2008

    The Discussion (page unavailable) says CDDO-Me inhibits IL-6-induced and constitutive JAK1 activity and supports a model in which binding at Cys1077 blocks JAK1 as an upstream effector of STAT3 phosphorylation. The ‘CDDO-Me interacts directly with JAK1’ section reports reduced binding after Cys1077 mutation and blocked JAK1-mediated STAT3 phosphorylation. Our copy does not specify Y705 as the phosphorylation site, so that detail is unsupported. (LLM, conf=0.86)

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Cited by

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Authors
Ahmad, R., Raina, D., Meyer, C., & Kufe, D.
Affiliations
  • Harvard University (US)
  • Reata Pharmaceuticals (United States) (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-04-15
Volume
68
Issue
8
Pages
2920-2926
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-07-3036
PMC
PMC3092292
OpenAlex
W2156126937
Cited by
120
References
2
Citations by year
2026: 5 · 2025: 6 · 2024: 1 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 8 · 2013: 9 · 2012: 9
FWCI
4.76
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ohio State University
  • Stony Brook University
  • National Cancer Institute (R01CA042802, R01CA098628, CA42802, P50CA100707, CA100707, CA98628)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
JAK1 inhibition, STAT3 inhibition, JAK1/STAT3 signaling pathway, interleukin-6, cysteine alkylation, thiol adducts, STAT3 dimerization, apoptosis, redox homeostasis
MeSH terms
Interleukin-6 Inhibitors, Biotin, Breast Neoplasms, Female, HeLa Cells, Humans, Oleanolic Acid, Protein Binding, Interleukin-6, Genes, Reporter, Dimerization, Cell Line, Tumor, STAT3 Transcription Factor, Janus Kinase 1

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