Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability
Glioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes w...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00662/full |
| _version_ | 1819011574063431680 |
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| author | Kevin L. Sheng Kevin J. Pridham Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Samy Lamouille Samy Lamouille Samy Lamouille Robin T. Varghese |
| author_facet | Kevin L. Sheng Kevin J. Pridham Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Samy Lamouille Samy Lamouille Samy Lamouille Robin T. Varghese |
| author_sort | Kevin L. Sheng |
| collection | DOAJ |
| description | Glioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes were identified as survival genes in 15 glioblastoma cell lines. RAN, member RAS oncogene family (RAN) was expressed in glioblastoma at the highest level among all candidates based upon cDNA microarray data. However, Kaplan-Meier survival analysis did not show any correlation between RAN mRNA levels and patient survival. Because RAN is a small GTPase that regulates nuclear transport controlled by karyopherin subunit beta 1 (KPNB1), RAN was further analyzed together with KPNB1. Indeed, GBM patients with high levels of RAN also had more KPNB1 and levels of KPNB1 alone did not relate to patient prognosis. Through a Cox multivariate analysis, GBM patients with high levels of RAN and KPNB1 showed significantly shorter life expectancy when temozolomide and promoter methylation of O6-methylguanine DNA methyltransferase were used as covariates. These results indicate that RAN and KPNB1 together are associated with drug resistance and GBM poor prognosis. Furthermore, the functional blockade of RAN and KPNB1 by importazole remarkably suppressed cell viability and activated apoptosis in GBM cells expressing high levels of RAN, while having a limited effect on astrocytes and GBM cells with undetectable RAN. Together, our results demonstrate that RAN activity is important for GBM survival and the functional blockade of RAN/KPNB1 is an appealing therapeutic approach. |
| first_indexed | 2024-12-21T01:30:19Z |
| format | Article |
| id | doaj.art-37b4dcbfe293483a99f08da204f3c1d6 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T01:30:19Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-37b4dcbfe293483a99f08da204f3c1d62022-12-21T19:20:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-01-01810.3389/fonc.2018.00662423014Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell ViabilityKevin L. Sheng0Kevin J. Pridham1Zhi Sheng2Zhi Sheng3Zhi Sheng4Zhi Sheng5Zhi Sheng6Samy Lamouille7Samy Lamouille8Samy Lamouille9Robin T. Varghese10Fralin Biomedical Research Institute at VTC, Roanoke, VA, United StatesFralin Biomedical Research Institute at VTC, Roanoke, VA, United StatesFralin Biomedical Research Institute at VTC, Roanoke, VA, United StatesDepartment of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, United StatesVirginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, United StatesWake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, United StatesFaculty of Health Science, Virginia Tech, Blacksburg, VA, United StatesFralin Biomedical Research Institute at VTC, Roanoke, VA, United StatesBasic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, United StatesDepartment of Biological Sciences, College of Science, Virginia Tech, Blacksburg, VA, United StatesDepartment of Biological Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA, United StatesGlioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes were identified as survival genes in 15 glioblastoma cell lines. RAN, member RAS oncogene family (RAN) was expressed in glioblastoma at the highest level among all candidates based upon cDNA microarray data. However, Kaplan-Meier survival analysis did not show any correlation between RAN mRNA levels and patient survival. Because RAN is a small GTPase that regulates nuclear transport controlled by karyopherin subunit beta 1 (KPNB1), RAN was further analyzed together with KPNB1. Indeed, GBM patients with high levels of RAN also had more KPNB1 and levels of KPNB1 alone did not relate to patient prognosis. Through a Cox multivariate analysis, GBM patients with high levels of RAN and KPNB1 showed significantly shorter life expectancy when temozolomide and promoter methylation of O6-methylguanine DNA methyltransferase were used as covariates. These results indicate that RAN and KPNB1 together are associated with drug resistance and GBM poor prognosis. Furthermore, the functional blockade of RAN and KPNB1 by importazole remarkably suppressed cell viability and activated apoptosis in GBM cells expressing high levels of RAN, while having a limited effect on astrocytes and GBM cells with undetectable RAN. Together, our results demonstrate that RAN activity is important for GBM survival and the functional blockade of RAN/KPNB1 is an appealing therapeutic approach.https://www.frontiersin.org/article/10.3389/fonc.2018.00662/fullRANglioblastomaimportazolecell survivalglioblastoma prognosisKPNB1 |
| spellingShingle | Kevin L. Sheng Kevin J. Pridham Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Zhi Sheng Samy Lamouille Samy Lamouille Samy Lamouille Robin T. Varghese Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability Frontiers in Oncology RAN glioblastoma importazole cell survival glioblastoma prognosis KPNB1 |
| title | Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability |
| title_full | Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability |
| title_fullStr | Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability |
| title_full_unstemmed | Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability |
| title_short | Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability |
| title_sort | functional blockade of small gtpase ran inhibits glioblastoma cell viability |
| topic | RAN glioblastoma importazole cell survival glioblastoma prognosis KPNB1 |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00662/full |
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