The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition
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 mutat...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/20/5029 |
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| author | Emma L. Hornick Laura L. Stunz Shakoora Sabree Xiaosheng Wu Thomas E. Witzig Gail A. Bishop |
| author_facet | Emma L. Hornick Laura L. Stunz Shakoora Sabree Xiaosheng Wu Thomas E. Witzig Gail A. Bishop |
| author_sort | Emma L. Hornick |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:32:21Z |
| format | Article |
| id | doaj.art-aa8ac7cc5eb349cf9bc37067e45da7a5 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:32:21Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-aa8ac7cc5eb349cf9bc37067e45da7a52023-11-23T23:20:46ZengMDPI AGCancers2072-66942022-10-011420502910.3390/cancers14205029The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 InhibitionEmma L. Hornick0Laura L. Stunz1Shakoora Sabree2Xiaosheng Wu3Thomas E. Witzig4Gail A. Bishop5Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242, USADepartment of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242, USAGraduate Program in Immunology and MSTP Program, The University of Iowa, Iowa City, IA 52242, USADivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USADivision of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USADepartment of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242, USATNF 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.https://www.mdpi.com/2072-6694/14/20/5029B cell lymphomaB cell survivallymphomagenesisGSK3TRAF3 |
| spellingShingle | Emma L. Hornick Laura L. Stunz Shakoora Sabree Xiaosheng Wu Thomas E. Witzig Gail A. Bishop The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition Cancers B cell lymphoma B cell survival lymphomagenesis GSK3 TRAF3 |
| title | The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition |
| title_full | The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition |
| title_fullStr | The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition |
| title_full_unstemmed | The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition |
| title_short | The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition |
| title_sort | tumor suppressor protein traf3 modulates gsk3 activity and susceptibility of b lymphoma cells to gsk3 inhibition |
| topic | B cell lymphoma B cell survival lymphomagenesis GSK3 TRAF3 |
| url | https://www.mdpi.com/2072-6694/14/20/5029 |
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