IFN-β Down-Regulates the Expression of DNA Repair Gene <i>MGMT</i> and Sensitizes Resistant Glioma Cells to Temozolomide

Natsume, Atsushi; Ishii, Dai; Wakabayashi, Toshihiko; Takaya, Tomofumi; Hatano, Hitoshi; Mizuno, Masaaki; Yoshida, Jun

doi:10.1158/0008-5472.can-05-0036

Cited by 157 publications

(149 citation statements)

References 17 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…Previous evidence reported by our group and others has shown that IFN-β induced growth inhibition or apoptosis in a variety of neoplasms (12,(23)(24)(25). Recently, we reported that IFN-β induced the differentiation of GICs to cells with an oligodendrocyte-like phenotype (26).…”

Section: Ifn-β Downregulates Mir-21 Transcriptionmentioning

confidence: 72%

“…The source of the cell lines and the culture conditions have been reported previously (23). Glioma tissue samples were obtained from patients (nos.…”

Section: Glioma Cell Lines and Primary Tumor Sphere Culturesmentioning

confidence: 99%

“…Cell lysis and immunoblotting were done as described previously (23). Antibodies against the following proteins were used: PDCD4 (ab51495; Abcam), phosphorylated STAT3 (p-Ser727 …”

Section: Western Blottingmentioning

confidence: 99%

See 2 more Smart Citations

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-β may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-β. We analyzed the effect of IFN-β treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-β treatment reduced miR-21 expression in glioma cells markedly, and IFN-β administration suppressed the growth of glioma-initiating cell-derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-β, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-β-mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)-expressing vectors induced the IFN-β-mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-β and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in

show abstract

Section: Ifn-β Downregulates Mir-21 Transcriptionmentioning

confidence: 72%

“…The source of the cell lines and the culture conditions have been reported previously (23). Glioma tissue samples were obtained from patients (nos.…”

Section: Glioma Cell Lines and Primary Tumor Sphere Culturesmentioning

confidence: 99%

See 1 more Smart Citation

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, clinical research has revealed that the methylation status of the MGMT promoter is associated with the prognostic outcome of GBM patients treated with temozolomide (Hegi et al, 2005). Reduction of MGMT expression induced by p53 in GBM cells renders them sensitive to www.intechopen.com temozolomide (Natsume et al, 2005). It is reasonable to speculate that increased expression of p53 by GSK3 inhibition enhances temozolomide chemosensitivity through the reduction of MGMT (Miyashita et al, 2009a).…”

Section: Chemosensitivitymentioning

confidence: 99%

The Pivotal Roles of GSK3β in Glioma Biology

Nakada¹,

Minamoto²,

Pyko³

et al. 2011

Molecular Targets of CNS Tumors

View full text Add to dashboard Cite

“…To date, a number of methods have been described to inhibit MGMT; however, their significance in clinical use for the purpose of overcoming temozolomide resistance is still limited or unknown [3,37,38]. Here, we have shown that the molecular pathway linking MEK to MGMT expression could offer novel and rational targets for MGMT inactivation, specifically MEK (by SL327) and MDM2 (by Nutlin-3).…”

Section: Resultsmentioning

confidence: 88%

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

et al. 2011

View full text Add to dashboard Cite

Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O 6 -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS

show abstract

IFN-β Down-Regulates the Expression of DNA Repair Gene MGMT and Sensitizes Resistant Glioma Cells to Temozolomide

Cited by 157 publications

References 17 publications

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

The Pivotal Roles of GSK3β in Glioma Biology

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

Contact Info

Product

Resources

About