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Cited by 478Multiple Myeloma Research and TreatmentsPI3K/AKT/mTOR signaling in cancerCytokine Signaling Pathways and Interactions

Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma

Hideshima, Teru, Nakamura, Noriaki, Chauhan, Dharminder, Anderson, Kenneth C·2001·Oncogene
DOI 10.1038/sj.onc.1204833
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Abstract

Previous studies demonstrate that interleukin-6 (IL-6) mediates growth and survival in human multiple myeloma (MM) cells via the MEK/MAPK and JAK/STAT signaling pathways, respectively. IL-6 also confers protection against Dexamethasone (Dex)-induced apoptosis via activation of protein tyrosine phosphatase (SHP2). In the current study, we characterized IL-6 triggered phophatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) signaling in MM cells. IL-6 induces Akt/PKB phosphorylation in a time and dose dependent manner in MM.1S MM cells. IL-6 also induced phosphorylation of downstream targets of Akt, including Bad, GSK-3beta, and FKHR, confirming Akt activation. Inhibition of Akt activation by the PI3-K inhibitor LY294002 partially blocked IL-6 triggered MEK/MAPK activation and proliferation in MM.1S cells, suggesting cross-talk between PI3-K and MEK signaling. We demonstrate that Dex-induced apoptosis in MM.1S cells is mediated by downstream activation of caspase-9, with resultant caspase-3 cleavage; and conversely, that IL-6 triggers activation of PI3-K and its association with SHP2, inactivates caspase-9, and protects against Dex-induced apoptosis. LY294002 completely abrogates this signaling cascade, further confirming the importance of PI3-K/Akt signaling in conferring the protective effect of IL-6 against Dex-induced apoptosis. Finally, we show that IL-6 triggered PI3-K/Akt signaling in MM.1S cells inactivates forkhead transcriptional factor (FKHR), with related G1/S phase tran…

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Crossref · 10.1038/sj.onc.1204833

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  • IL-6 induces insulin resistance in hepatocytes and skeletal muscle cells.

    “Our findings are in accordance with previous reports that IL‐6 induces insulin resistance in hepatocytes and skeletal muscle cells. 34”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [34]

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Authors
Hideshima, T., Nakamura, N., Chauhan, D., & Anderson, K. C.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Harvard University (US)
Corresponding author
Anderson, Kenneth C
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2001-09-20
Volume
20
Issue
42
Pages
5991-6000
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/sj.onc.1204833
OpenAlex
W2007998678
Cited by
478
References
0
Citations by year
2026: 1 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 18 · 2020: 9 · 2019: 18 · 2018: 16 · 2017: 12 · 2016: 16 · 2015: 16 · 2014: 25 · 2013: 21 · 2012: 21
FWCI
13.95
Type
journal article
Language
en
Update notices
Open access
closed
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (P01-MH78378, R01MH050947)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, multiple myeloma, PI3K/Akt signaling, dexamethasone-induced apoptosis, SHP2, JAK/STAT signaling, caspase-9, caspase-3, forkhead transcription factor, p27, G1/S cell cycle arrest, LY294002, MM.1S cells, apoptosis resistance
MeSH terms
Cell Cycle, Chromones, Dexamethasone, Enzyme Activation, Enzyme Inhibitors, Humans, Morpholines, Multiple Myeloma, Phosphorylation, Proto-Oncogene Proteins, Tumor Cells, Cultured, Signal Transduction, Interleukin-6, Protein Tyrosine Phosphatases, Apoptosis, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Caspase 9, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Caspase Inhibitors

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