Targetable T-type Calcium Channels Drive Glioblastoma

Cancer Research
Ying ZhangRoger Abounader

Abstract

Glioblastoma (GBM) stem-like cells (GSC) promote tumor initiation, progression, and therapeutic resistance. Here, we show how GSCs can be targeted by the FDA-approved drug mibefradil, which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSCs. Analyses of the The Cancer Genome Atlas and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3.2 was sufficient to inhibit the growth, survival, and stemness of GSCs and also sensitized them to temozolomide chemotherapy. Proteomic and transcriptomic analyses revealed that Cav3.2 inhibition altered cancer signaling pathways and gene transcription. Cav3.2 inhibition suppressed GSC growth in part by inhibiting prosurvival AKT/mTOR pathways and stimulating proapoptotic survivin and BAX pathways. Furthermore, Cav3.2 inhibition decreased expression of oncogenes (PDGFA, PDGFB, and TGFB1) and increased expression of tumor suppressor genes (TNFRSF14 and HSD17B14). Oral administration of mibefradil inhibited growth of GSC-derived GBM murine xenografts, prolonged host survival, an...Continue Reading

References

Jan 1, 1990·Current Topics in Cellular Regulation·H Rasmussen, J E Rasmussen
Oct 10, 1986·Science·E Rozengurt
Oct 1, 1994·Cell Calcium·E Roche, M Prentki
Mar 9, 1995·Nature·D O Morgan
Feb 1, 1993·Endocrine Reviews·K P Lu, A R Means
Jan 5, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·R B Silver
May 24, 2000·Cellular and Molecular Life Sciences : CMLS·M Brini, E Carafoli
Feb 24, 2001·Clinical Cardiology·D Tzivoni
Nov 19, 2004·Nature·Sheila K SinghPeter B Dirks
Apr 13, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jann N SarkariaC David James
Feb 5, 2009·Molecular Cancer Therapeutics·Yunqing LiRoger Abounader
Oct 29, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aurélie ErnstBernhard Radlwimmer
Feb 6, 2010·Stem Cells·Frank PajonkWilliam H McBride
May 31, 2011·Progress in Neurobiology·Michelle R Lyons, Anne E West
Jun 30, 2011·Cancer Research·Julie MathieuHannele Ruohola-Baker
Nov 4, 2011·American Journal of Physiology. Cell Physiology·José A Rodríguez-GómezJosé López-Barneo
Nov 15, 2011·Methods in Molecular Biology·Mariaelena PierobonEmanuel F Petricoin
Feb 23, 2012·British Journal of Pharmacology·Giorgio SantoniMassimo Nabissi
Mar 6, 2012·Cancer Prevention Research·Janine G EinspahrEmanuel F Petricoin
Jul 24, 2012·The Journal of Biological Chemistry·Gregory R MonteithSarah J Roberts-Thomson
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Jan 5, 2013·Biochemical Pharmacology·Nicholas C K ValerieJaroslaw Dziegielewski
Jan 28, 2014·British Journal of Pharmacology·I AzimiG R Monteith
Mar 4, 2014·Current Pathobiology Reports·Spencer W CrowderHak-Joon Sung
Aug 26, 2014·Biochimica Et Biophysica Acta·Teneale A StewartGregory R Monteith
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
May 12, 2015·Cell Reports·Masahiro HitomiJustin D Lathia
May 27, 2015·Cancers·Vidhya R RaoSaverio Gentile
Jun 15, 2015·Biochimica Et Biophysica Acta·Nadine Déliot, Bruno Constantin
Jun 26, 2015·Genes & Development·Justin D LathiaJeremy N Rich
Jan 20, 2016·Nature Reviews. Neurology·Patrick Y Wen, David A Reardon
Mar 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Chuanzhao ZhangGregg L Semenza
Apr 5, 2016·Current Opinion in Pharmacology·Saverio Marchi, Paolo Pinton

❮ Previous
Next ❯

Citations

Apr 21, 2018·Genes & Development·Joyce V LeeKathryn E Wellen
Nov 29, 2017·Journal of Experimental & Clinical Cancer Research : CR·Claudia AbbruzzeseMarco G Paggi
Jan 30, 2019·Cancers·Ahmed MakladIman Azimi
Sep 23, 2018·Breast Cancer Research and Treatment·Anamika Bhargava, Sumit Saha
Jan 9, 2019·Frontiers in Molecular Neuroscience·Isabelle NéantCatherine Leclerc
Feb 13, 2020·Cancers·Carla BarcelóAnna Macià
Sep 12, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nichola CruickshanksRoger Abounader
Oct 4, 2020·Molecular Cancer Therapeutics·Takeshi TakayasuLeomar Y Ballester
Jan 19, 2018·Cancer Research·Marta C SallánCarles Cantí
Oct 25, 2020·Cancers·Michaela GriffinStuart Smith
Dec 8, 2020·Frontiers in Cellular Neuroscience·Valérie CoronasBruno Constantin
Jan 10, 2021·International Journal of Molecular Sciences·Jaroslaw SzczepaniakMarta Grodzik
Apr 11, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Lía AlzaCarles Cantí
Apr 4, 2021·International Journal of Molecular Sciences·Olga García-Minguillán, Ceferino Maestú
Jan 14, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Alban GiraultHalima Ouadid-Ahidouch
May 20, 2019·Cell Calcium·Elodie TerriéBruno Constantin
Dec 27, 2019·The Journal of Investigative Dermatology·Carla BarcelóAnna Macià
Dec 20, 2020·Cancer Treatment and Research Communications·Mohammed A AzabAhmed Y Azzam
May 21, 2021·Frontiers in Pharmacology·Yan ChangZui Pan
Jun 8, 2021·Frontiers in Oncology·José A Carlos-EscalanteTalia Wegman-Ostrosky
Jul 2, 2021·Oncotarget·Roger Abounader, David Schiff
Jun 22, 2021·Frontiers in Cellular Neuroscience·Jae-Seon SoKyung-Seok Han
Jul 22, 2021·The FEBS Journal·Ling WuLiang Zhao
Apr 17, 2019·ACS Applied Materials & Interfaces·Shan-Wen HuJing-Juan Xu
Oct 16, 2021·Frontiers in Cell and Developmental Biology·Cha LinXinjian Liu

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Stem Cells in Glioblastoma

Glioblastoma is the most common and aggressive type of brain tumor. It contains a population of tumor initiating stem cell-like cells known as cancer stem cells. Investigations are ongoing into these cancer stem cells found in these solid tumors which are highly resistance to treatment. Here is the latest research on cancer stem cells in glioblastoma.

Cancer -Omics

A variety of different high-throughput technologies can be used to identify the complete catalog of changes that characterize the molecular profile of cohorts of tumor samples. Discover the latest insights gained from cancer 'omics' in this feed.