Abstract
Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K–Akt pathway, a pro-tumorigenic signaling cascade that contributes to pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human glioblastoma (GBM). Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers, SOX2 and nestin, and migration on the brain slice and induced the expression of neural differentiation markers glial fibrillary acidic protein/βIII Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y et al. (2005). A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem 280: 18525–18535.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760.
Brazil DP, Park J, Hemmings BA . (2002). PKB binding proteins. Getting in on the Akt. Cell 111: 293–303.
Castellino RC, Durden DL . (2007). Mechanisms of disease: the PI3K-Akt-PTEN signaling node--an intercept point for the control of angiogenesis in brain tumors. Nat Clin Pract Neurol 3: 682–693.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M et al. (2009). Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron 63: 774–787.
Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K et al. (2005). Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9: 389–402.
Eyler CE, Foo WC, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN . (2008). Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 26: 3027–3036.
Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R et al. (2008). Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27: 2897–2909.
Hay N . (2005). The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8: 179–183.
Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100: 15178–15183.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB . (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4: 988–1004.
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M et al. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1: 313–323.
Jiang P, Enomoto A, Jijiwa M, Kato T, Hasegawa T, Ishida M et al. (2008). An actin-binding protein Girdin regulates the motility of breast cancer cells. Cancer Res 68: 1310–1318.
Kato H, Ishida J, Nagano K, Honjo K, Sugaya T, Takeda N et al. (2008). Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells. Lab Invest 88: 731–739.
Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N et al. (2009). DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63: 761–773.
Kitamura T, Asai N, Enomoto A, Maeda K, Kato T, Ishida M et al. (2008). Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat Cell Biol 10: 329–337.
Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9: 391–403.
Luo J, Manning BD, Cantley LC . (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262.
Matsumoto K, Arao T, Tanaka K, Kaneda H, Kudo K, Fujita Y et al. (2009). mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res 69: 7160–7164.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.
Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD et al. (2009). Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28: 3949–3959.
Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO . (2001). Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 61: 6674–6678.
Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.
Wakimoto H, Kesari S, Farrell CJ, Curry Jr WT, Zaupa C, Aghi M et al. (2009). Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res 69: 3472–3481.
Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. (2004). Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: 332–337.
Yuki K, Natsume A, Yokoyama H, Kondo Y, Ohno M, Kato T et al. (2009). Induction of oligodendrogenesis in glioblastoma-initiating cells by IFN-mediated activation of STAT3 signaling. Cancer Lett 284: 71–79.
Zhang B, Gu F, She C, Guo H, Li W, Niu R et al. (2009). Reduction of Akt2 inhibits migration and invasion of glioma cells. Int J Cancer 125: 585–595.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website )
Supplementary information
Rights and permissions
About this article
Cite this article
Natsume, A., Kato, T., Kinjo, S. et al. Girdin maintains the stemness of glioblastoma stem cells. Oncogene 31, 2715–2724 (2012). https://doi.org/10.1038/onc.2011.466
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2011.466
Keywords
This article is cited by
-
Girdin acts as an oncogene in gastric cancer by regulating AKT/GSK3β/β-catenin signaling
Functional & Integrative Genomics (2023)
-
RETRACTED ARTICLE: Expression and prognostic value of the aldehyde dehydrogenase 1 (ALDH1) and N-myc downstream regulated gene 2 (NDRG2) as potential markers in human astrocytomas
Tumor Biology (2016)
-
Loss of Dlg5 expression promotes the migration and invasion of prostate cancer cells via Girdin phosphorylation
Oncogene (2015)
-
Neuropeptides of the VIP family inhibit glioblastoma cell invasion
Journal of Neuro-Oncology (2015)
-
Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer
Molecular Biology Reports (2012)