The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition

Emma L. Hornick; Laura L. Stunz; Shakoora Sabree; Xiaosheng Wu; Thomas E. Witzig; Gail A. Bishop

doi:10.3390/cancers14205029

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The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition

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The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition

Emma L. Hornick, Laura L. Stunz, Shakoora Sabree, Xiaosheng Wu, Thomas E. Witzig and Gail A. Bishop

Cancers, Vol.14(20), p.5029

10/14/2022

DOI: 10.3390/cancers14205029

PMCID: PMC9599470

PMID: 36291813

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Abstract

TNF receptor-associated factor 3 (TRAF3) is an adapter protein that inhibits many signals that promote B cell survival and activation. Mice with a B cell-specific TRAF3 deficiency and humans with a rare haploinsufficiency in TRAF3 have enhanced development of BCLs as they age. Loss-of-function mutations in TRAF3 are common in B cell malignancies. Recent studies show that pharmacological inhibition of the enzyme glycogen synthase kinase 3 (GSK3), which regulates cellular growth, survival, and metabolism, inhibits growth and survival of BCL-derived B cells. In this study, we found that TRAF3 and GSK3 associated in B cells. The relative levels of TRAF3 in BCL cell lines correlated positively with the ratio of inactive to total GSK3β, and negatively correlated with susceptibility to GSK3 inhibition by the GSK3 inhibitory drug 9-ING-41, currently in clinical trials. Uniquely in BCLs with low TRAF3, GSK3 inhibition caused increased loss of the TRAF3-regulated, anti-apoptotic protein Mcl-1. GSK3 inhibition also blocked hyperresponsiveness to IL-6 receptor signaling in TRAF3-deficient BCL cells. Together, these results support the utility of 9-ING-41 as a treatment for BCL, and suggest that a decrease or loss of TRAF3 in BCLs could act as a biomarker for increased susceptibility to GSK3 inhibitor treatment.

B cell lymphoma

B cell survival

GSK3

lymphomagenesis

TRAF3

Details

Title: Subtitle: The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition
Creators: Emma L. Hornick - University of Iowa
Laura L. Stunz - University of Iowa
Shakoora Sabree - University of Iowa
Xiaosheng Wu - Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242, USA Veterans Administration Medical Center, Iowa City, IA 52242, USA Graduate Program in Immunology and MSTP Program, The University of Iowa, Iowa City, IA 52242, USA Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Thomas E. Witzig - University of Iowa
Gail A. Bishop - Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242, USA Veterans Administration Medical Center, Iowa City, IA 52242, USA Graduate Program in Immunology and MSTP Program, The University of Iowa, Iowa City, IA 52242, USA Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Resource Type: Journal article
Publication Details: Cancers, Vol.14(20), p.5029
DOI: 10.3390/cancers14205029
PMID: 36291813
PMCID: PMC9599470
NLM abbreviation: Cancers (Basel)
ISSN: 2072-6694
eISSN: 2072-6694
Publisher: MDPI
Grant note: 2I01BX001702 / the Veterans Administration P50 CA097274; R01 AI162656; P30CA086862; T32 AI007260; T32 HL007344 / the National Institutes of Health
Language: English
Date published: 10/14/2022
Academic Unit: Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984307557502771

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