Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin

Tamase, Akira; Muraguchi, Teruyuki; Naka, Kazuhito; Tanaka, Shingo; Kinoshita, Masashi; Hoshii, Takayuki; Ohmura, Masako; Shugo, Haruhiko; Ooshio, Takako; Nakada, Mitsutoshi; Sawamoto, Kazunobu; Onodera, Masafumi; Matsumoto, Kunio; Oshima, Masanobu; Asano, Masahide; Saya, Hideyuki; Okano, Hideyuki; Suda, Toshio; Hamada, Jun Ichiro; Hirao, Atsushi

doi:10.1073/pnas.0905016106

Cited by 77 publications

(71 citation statements)

References 31 publications

(38 reference statements)

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“…In the present study, we have shown that inhibition of GSK3b attenuates the migration and invasion of glioblastoma cells in vitro, as well as the invasion of malignant glioma cells in an animal model that recapitulates human glioblastoma (24). These effects were associated with alterations in molecular pathways mediated by FAK, GEFs/Rac1, and JNK.…”

Section: Discussionmentioning

confidence: 72%

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Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Chikano

Domoto

Furuta

et al. 2015

Molecular Cancer Therapeutics

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The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3b (GSK3b), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3b compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3b also contributes to the highly invasive nature of glioblastoma. The effects of GSK3b inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3b attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3b as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo-and radioresistance. Mol Cancer Ther; 14(2); 564-74. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 72%

“…These were then transplanted into the brains of wild-type mice, as described in our previous study (24). Brain tumors developed in this mouse model as early as 20 days after transplantation, with most mice dying within 40 days.…”

Section: Animal Study Immunohistochemical and Biochemical Analysismentioning

confidence: 99%

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Chikano

Domoto

Furuta

et al. 2015

Molecular Cancer Therapeutics

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“…In agreement with the Transwell assay, the wound healing assay showed significantly delayed the closure of the knockdown group compared to non-transfected ells after scratch assay ( Figure 5A). Tsai and McKay (2002) had identified NS, a novel p53-binding protein that was abundantly present in stem cells and stem cell-enriched tissues (Kafienah et al, 2006;Tamase et al, 2009). Interestingly, both NS mRNA and protein are absent in adult differentiated cells/tissues, although highly expressed in different human cancer cell lines.…”

Section: Inhibition Of Ns Generation Decreased Cell Motility and Invamentioning

confidence: 99%

“…NS possesses two putative GTP-binding motifs, and has been proposed as a marker for an undifferentiated or dedifferentiating state and for TICs in highly aggressive brain tumors (Kafienah et al, 2006;Tamase et al, 2009). The level of NS decreases drastically prior to cell cycle exit upon differentiation of the stem cells, suggesting that this protein may be an imperative protein for regulating the proliferation of stem cells and cancer cells, and in maintenance of their undifferentiated features (Jafarnejad et al, 2008;Nomura et al, 2009;Gao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

In vitro Study of Nucleostemin as a Potential Therapeutic Target in Human Breast Carcinoma SKBR-3 Cells

Guo

Liao²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Although nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis and expression has been observed in some types of human cancer and stem cells, the molecular mechanisms involved in mediation of cell proliferation and cell cycling remains largely elusive. The aim of the present study was to evaluate NS as a potential target for gene therapy of human breast carcinoma by investigating NS gene expression and its effects on SKBR-3 cell proliferation and apoptosis. NS mRNA and protein were both found to be highly expressed in all detected cancer cell lines. The apoptotic rate of the pcDNA3.1-NS-Silencer group (12.1-15.4±3.8%) was significantly higher than those of pcDNA3.1-NS (7.2-12.0±1.7%) and non-transfection groups (4.1-6.5±1.8%, P<0.01). MTT assays showed the knockdown of NS expression reduced the proliferation rate of SKBR-3 cells significantly. Matrigel invasion and wound healing assays indicated that the number of invading cells was significantly decreased in the pcDNA3.1-NS-siRNA group (P<0.01), but there were no significant difference between non-transfected and over-expression groups (P>0.05). Moreover, RNAi-mediated NS downregulation induced SKBR-3 cell G1 phase arrest, inhibited cell proliferation, and promoted p53 pathway-mediated cell apoptosis in SKBR-3 cells. NS might thus be an important regulator in the G2/M check point of cell cycle, blocking SKBR-3 cell progression through the G1/S phase. On the whole, these results suggest NS might be a tumor suppressor and important therapeutic target in human cancers.

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“…Alternatively, CSCs were identified in a murine brain tumor population by expressing EGFP under the control of nucleostemin promoter (a p53 mediate cell cycle modulator often expressed by highly proliferative cells) (Tamase, Muraguchi et al 2009). Furthermore, screening of BTSCs using flow-cytometry and Elisa have identified CD133, MMP-9, nestin, Pax6, Math-1, musashi-1, BMI-1, CXCR4, CX3CR1, c-Myc and Sox2 expressing BTSCs from both gliomas and medulloblastomas (Tamase, Muraguchi et al 2009, Cox, Wilder et al 2013, Sullivan, Nahed et al 2014). 1) High expression acts as an independent prognosis marker for malignant gliomas (Krogh Petersen, Jensen et al 2016).…”

Section: Diagnostic Approach To Identify Btscsmentioning

confidence: 99%

Brain Tumor Treatment: 2017 Update

Chakraborty¹,

Han²,

Faltas³

et al. 2018

CCO

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Malignant brain tumors are a heterogeneous group of diseases arising from different cell types that affect both adults and children. The high recurrence rate of malignant brain tumors typically is due to reappearance of focal masses, indicating that a sub population of tumor cells are insensitive to current therapies and may be responsible for reinitiating tumor growth. It is generally agreed that the resistant tumor cells are comprised of cancer stem cells or tumor-initiating cells. While brain tumor stem cells (BTSCs) were first isolated within the last decade, much of the early research has been focused on identifying the BTSC markers and therapeutic targets. The challenge however, is to translate this knowledge to therapeutics. In the current review, we survey the remedial strategies to target BTSCs, which includes diagnostic, pharmacologic, immunologic, viral, and post-transcriptional approaches.

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Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin

Cited by 77 publications

References 31 publications

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

In vitro Study of Nucleostemin as a Potential Therapeutic Target in Human Breast Carcinoma SKBR-3 Cells

Brain Tumor Treatment: 2017 Update

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