Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner
Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere w...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-07-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324000834 |
| _version_ | 1797200873040904192 |
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| author | Jia Tian Julianne C. Mallinger Ping Shi Dahao Ling Loic P. Deleyrolle Min Lin Habibeh Khoshbouei Matthew R. Sarkisian |
| author_facet | Jia Tian Julianne C. Mallinger Ping Shi Dahao Ling Loic P. Deleyrolle Min Lin Habibeh Khoshbouei Matthew R. Sarkisian |
| author_sort | Jia Tian |
| collection | DOAJ |
| description | Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B+ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo. |
| first_indexed | 2024-04-24T07:38:34Z |
| format | Article |
| id | doaj.art-57ef9904b530417fbe1d5d0a9438b3c5 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-24T07:38:34Z |
| publishDate | 2024-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-57ef9904b530417fbe1d5d0a9438b3c52024-04-20T04:17:19ZengElsevierTranslational Oncology1936-52332024-07-0145101956Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent mannerJia Tian0Julianne C. Mallinger1Ping Shi2Dahao Ling3Loic P. Deleyrolle4Min Lin5Habibeh Khoshbouei6Matthew R. Sarkisian7Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neurosurgery, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA; Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL 32610, USA; Corresponding author.Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B+ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.http://www.sciencedirect.com/science/article/pii/S1936523324000834Tumor Treating FieldsAURKAAURKBPrimary ciliumAutophagyARL13B |
| spellingShingle | Jia Tian Julianne C. Mallinger Ping Shi Dahao Ling Loic P. Deleyrolle Min Lin Habibeh Khoshbouei Matthew R. Sarkisian Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner Translational Oncology Tumor Treating Fields AURKA AURKB Primary cilium Autophagy ARL13B |
| title | Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner |
| title_full | Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner |
| title_fullStr | Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner |
| title_full_unstemmed | Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner |
| title_short | Aurora kinase A inhibition plus Tumor Treating Fields suppress glioma cell proliferation in a cilium-independent manner |
| title_sort | aurora kinase a inhibition plus tumor treating fields suppress glioma cell proliferation in a cilium independent manner |
| topic | Tumor Treating Fields AURKA AURKB Primary cilium Autophagy ARL13B |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324000834 |
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