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Author Li, M.; Xiao, A.; Floyd, D.; Olmez, I.; Lee, J.; Godlewski, J.; Bronisz, A.; Bhat, K.P.L.; Sulman, E.P.; Nakano, I.; Purow, B.
Title CDK4/6 inhibition is more active against the glioblastoma proneural subtype Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 33 Pages 55319-55331
Keywords Cdk4/6; glioblastoma; mesenchymal; palbociclib; proneural
Abstract Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy.
Address Neuro-Oncology Division, Department of Neurology, University of Virginia, Charlottesville, VA, USA
Corporate Author Thesis
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Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
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ISSN (down) 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28903422 Approved no
Call Number ref @ user @ Serial 96569
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Author Oliva, C.R.; Zhang, W.; Langford, C.; Suto, M.J.; Griguer, C.E.
Title Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 23 Pages 37568-37583
Keywords chlorpromazine; cytochrome c oxidase; glioblastoma; inhibitor; stem cells
Abstract Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice. Recently, experimental evidence revealed the anti-proliferative activity of chlorpromazine against colon and brain tumors. Here, we used chemoresistant patient-derived glioma stem cells and chemoresistant human glioma cell lines to investigate the effects of chlorpromazine against chemoresistant glioma. Chlorpromazine selectively and significantly inhibited proliferation in chemoresistant glioma cells and glioma stem cells. Mechanistically, chlorpromazine inhibited cytochrome c oxidase (CcO, complex IV) activity from chemoresistant but not chemosensitive cells, without affecting other mitochondrial complexes. Notably, our previous studies revealed that the switch to chemoresistance in glioma cells is accompanied by a switch from the expression of CcO subunit 4 isoform 2 (COX4-2) to COX4-1. In this study, chlorpromazine induced cell cycle arrest selectively in glioma cells expressing COX4-1, and computer-simulated docking studies indicated that chlorpromazine binds more tightly to CcO expressing COX4-1 than to CcO expressing COX4-2. In orthotopic mouse brain tumor models, chlorpromazine treatment significantly increased the median overall survival of mice harboring chemoresistant tumors. These data indicate that chlorpromazine selectively inhibits the growth and proliferation of chemoresistant glioma cells expressing COX4-1. The feasibility of repositioning chlorpromazine for selectively treating chemoresistant glioma tumors should be further explored.
Address Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (down) 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28455961 Approved no
Call Number ref @ user @ Serial 96587
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Author Roy, A.; Attarha, S.; Weishaupt, H.; Edqvist, P.-H.; Swartling, F.J.; Bergqvist, M.; Siebzehnrubl, F.A.; Smits, A.; Ponten, F.; Tchougounova, E.
Title Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 15 Pages 24815-24827
Keywords Cd44; Zeb1; glioma; mast cell; serglycin
Abstract Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.
Address Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (down) 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28445977 Approved no
Call Number ref @ user @ Serial 96590
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Author Brodie, S.; Lee, H.K.; Jiang, W.; Cazacu, S.; Xiang, C.; Poisson, L.M.; Datta, I.; Kalkanis, S.; Ginsberg, D.; Brodie, C.
Title The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 19 Pages 31785-31801
Keywords Talnec2; glioblastoma; glioma stem cells; long non-cording RNAs; mesenchymal transformation
Abstract Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.
Address Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (down) 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28423669 Approved no
Call Number ref @ user @ Serial 96594
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Author Sullivan, K.E.; Rojas, K.; Cerione, R.A.; Nakano, I.; Wilson, K.F.
Title The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 14 Pages 22325-22343
Keywords Aldehyde Oxidoreductases/genetics/*metabolism; Biomarkers, Tumor/metabolism; Brain Neoplasms/genetics/*metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine/analogs & derivatives/pharmacology; GTP-Binding Proteins/genetics/*metabolism; Gene Expression Regulation, Neoplastic; Glioma/genetics/*metabolism; Humans; Mesenchymal Stromal Cells/*physiology; Neoplastic Stem Cells/*physiology; RNA, Small Interfering/genetics; Stem Cells/*physiology; Transglutaminases/genetics/*metabolism; Tretinoin/metabolism; Up-Regulation; aldehyde dehydrogenase; cancer stem cells; glioblastoma; retinoic acid; tissue transglutaminase
Abstract Tissue transglutaminase (tTG), a dual-function enzyme with GTP-binding and acyltransferase activities, has been implicated in the survival and chemotherapy resistance of aggressive cancer cells and cancer stem cells, including glioma stem cells (GSCs). Using a model system comprising two distinct subtypes of GSCs referred to as proneural (PN) and mesenchymal (MES), we find that the phenotypically aggressive and radiation therapy-resistant MES GSCs exclusively express tTG relative to PN GSCs. As such, the self-renewal, proliferation, and survival of these cells was sensitive to treatment with tTG inhibitors, with a benefit being observed when combined with the standard of care for high grade gliomas (i.e. radiation or temozolomide). Efforts to understand the molecular drivers of tTG expression in MES GSCs revealed an unexpected link between tTG and a common marker for stem cells and cancer stem cells, Aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3, as well as other members of the ALDH1 subfamily, can function in cells as a retinaldehyde dehydrogenase to generate retinoic acid (RA) from retinal. We show that the enzymatic activity of ALDH1A3 and its product, RA, are necessary for the observed expression of tTG in MES GSCs. Additionally, the ectopic expression of ALDH1A3 in PN GSCs is sufficient to induce the expression of tTG in these cells, further demonstrating a causal link between ALDH1A3 and tTG. Together, these findings ascribe a novel function for ALDH1A3 in an aggressive GSC phenotype via the up-regulation of tTG, and suggest the potential for a similar role by ALDH1 family members across cancer types.
Address Department of Molecular Medicine, Cornell University, Ithaca, NY, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (down) 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28423611 Approved no
Call Number ref @ user @ Serial 96595
Permanent link to this record