Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM
An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interle...
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doaj-2c3b6470cd93457e987e993caefb68142021-09-19T04:55:53ZengElsevierTranslational Oncology1936-52332021-11-011411101192Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBMSamantha M. Wightman0Tyler J. Alban1Xing Chen2Justin D. Lathia3Yuxin Wang4George R. Stark5Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United StatesDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United States; Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Cleveland, OH, United States; Department of Inflammation and Immunity, Lerner Research Insititute, Cleveland Clinic Foundation, Cleveland, OH, United StatesDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United States; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United StatesDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United States; Co-corresponding authors.Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States; Case Comprehensive Cancer Center, Cleveland, OH, United States; Co-corresponding authors.An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interleukin-6 (IL6)-STAT3 signaling axis has been studied extensively in inflammation and cancer. However, it is not completely understood how high levels of activated STAT3 are sustained in tumors. Previously, we identified a novel mechanism of biphasic activation of STAT3 in response to gp130-linked cytokines, including IL6, in which activation of STAT3 is prolonged by circumventing the negative regulatory mechanisms induced by its initial activationTo target prolonged STAT3 activation, we used the small molecule inhibitor bazedoxifene (BZA), which blocks formation of the IL6 receptor-gp130 complex. Glioma stem-like cells (GSCs) are more tumorigenic and more resistant to therapy. STAT3 is a key driver of the expression of stem cell transcription factors, making it a therapeutically important target in GBM. We show that treating GSCs with BZA decreases their self-renewal capacity and the expression of GSC markers in vitro. Additionally, BZA crosses the blood-brain barrier and confers a survival advantage in an orthotopic syngeneic mouse model of GBM. Although IL6-STAT3 signaling is important for GSC survival, a therapeutic agent that inhibits this pathway without toxicity has yet to be identified. Our findings reveal a mechanism of sustained STAT3 signaling in GBM and reveal its role in GSC maintenance, and we identify BZA as a novel candidate for treating GBM.http://www.sciencedirect.com/science/article/pii/S1936523321001844GlioblastomaIL6STAT3BazedoxifeneGlioma stem cellsCancer stem cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Samantha M. Wightman Tyler J. Alban Xing Chen Justin D. Lathia Yuxin Wang George R. Stark |
spellingShingle |
Samantha M. Wightman Tyler J. Alban Xing Chen Justin D. Lathia Yuxin Wang George R. Stark Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM Translational Oncology Glioblastoma IL6 STAT3 Bazedoxifene Glioma stem cells Cancer stem cells |
author_facet |
Samantha M. Wightman Tyler J. Alban Xing Chen Justin D. Lathia Yuxin Wang George R. Stark |
author_sort |
Samantha M. Wightman |
title |
Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM |
title_short |
Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM |
title_full |
Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM |
title_fullStr |
Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM |
title_full_unstemmed |
Bazedoxifene inhibits sustained STAT3 activation and increases survival in GBM |
title_sort |
bazedoxifene inhibits sustained stat3 activation and increases survival in gbm |
publisher |
Elsevier |
series |
Translational Oncology |
issn |
1936-5233 |
publishDate |
2021-11-01 |
description |
An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interleukin-6 (IL6)-STAT3 signaling axis has been studied extensively in inflammation and cancer. However, it is not completely understood how high levels of activated STAT3 are sustained in tumors. Previously, we identified a novel mechanism of biphasic activation of STAT3 in response to gp130-linked cytokines, including IL6, in which activation of STAT3 is prolonged by circumventing the negative regulatory mechanisms induced by its initial activationTo target prolonged STAT3 activation, we used the small molecule inhibitor bazedoxifene (BZA), which blocks formation of the IL6 receptor-gp130 complex. Glioma stem-like cells (GSCs) are more tumorigenic and more resistant to therapy. STAT3 is a key driver of the expression of stem cell transcription factors, making it a therapeutically important target in GBM. We show that treating GSCs with BZA decreases their self-renewal capacity and the expression of GSC markers in vitro. Additionally, BZA crosses the blood-brain barrier and confers a survival advantage in an orthotopic syngeneic mouse model of GBM. Although IL6-STAT3 signaling is important for GSC survival, a therapeutic agent that inhibits this pathway without toxicity has yet to be identified. Our findings reveal a mechanism of sustained STAT3 signaling in GBM and reveal its role in GSC maintenance, and we identify BZA as a novel candidate for treating GBM. |
topic |
Glioblastoma IL6 STAT3 Bazedoxifene Glioma stem cells Cancer stem cells |
url |
http://www.sciencedirect.com/science/article/pii/S1936523321001844 |
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