Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

Kanzawa, Takao; Iwado, Eiji; Aoki, Hiroshi; Iwamaru, Arifumi; Hollingsworth, E. Faith; Sawaya, Raymond; Kondo, Seiji; Kondo, Yasuko

doi:10.1038/sj.onc.1209414

Cited by 52 publications

(41 citation statements)

References 49 publications

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“…However, in endogenous neural stem cells, Notch signaling may not be regulated by JNK, because JNK signaling appears to induce apoptosis in normal neural stem cells. 19,44 In addition, cellular proliferation of normal neural stem cells was not affected by the increase of NO levels, whereas NO led to the increase of glioma stem-like cell population. 54 Thus, the route of Notch signaling activation, NO/JNK/Notch may be distinctive pathway for the maintenance of glioma stem-like cells, implicating a novel therapeutic target for glioma stem-like cells without damaging endogenous neural stem cells.…”

Section: Discussionmentioning

confidence: 97%

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c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

Yoon

Kim

et al. 2012

Oncogene

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Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133 þ /Nestin þ population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposideand ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133 þ /Nestin þ cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

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Section: Discussionmentioning

confidence: 97%

“…19 JNK signaling-induced apoptosis was previously reported in rat neural stem cells. 44 Thus, in normal brain, activation of JNK signaling appears to induce apoptosis of neural stem cells. In contrast, JNK has been reported to be constitutively activated in malignant gliomas.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

Yoon

Kim

et al. 2012

Oncogene

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“…The cytotoxic effect of WP1066 or AG490 was determined using the Cell Proliferation Reagent WST-1 assay (Roche Applied Science, Indianapolis, IN, USA) as described previously (Kanzawa et al, 2006). Cells (7 Â 10 3 cells/well, 100 ml) were seeded in 96-well flat-bottomed plates and incubated overnight at 371C and in 5% CO 2 -95% air.…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…For cell cycle analysis, cells fixed with ice-cold 70% ethanol were stained with propidium iodide and reagents from the Cellular DNA Flow Cytometric Analysis Kit (Boehringer Mannheim, Indianapolis, IN, USA); they were then analysed for DNA content using a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA) as described previously (Kanzawa et al, 2006). The percentages of cells in the sub-G1, G1, S and G2/M populations were determined by CellQuest software (Becton Dickinson).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…After exposure to WP1066, cells were trypsinized and washed in cold phosphate-buffered saline (PBS), fixed in 70% ethanol and then stored at À201C for more than 2 h. To detect nuclei with fragmented DNA, which is characteristic of apoptosis, we performed a TUNEL assay using the ApopTag Plus Fluorescein In Situ Apoptosis Detection Kit (Chemicon International, Temecula, CA, USA) according to the manufacturer's instructions. Cells were analysed by flow cytometry using the FACScan cytometer as described previously (Kanzawa et al, 2006).…”

Section: Analysis Of Apoptosismentioning

confidence: 99%

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A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Zlojutro

Manz

Rangaswamy

et al. 2010

American J of Med Genetics Pt B

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Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype – frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher’s combined P = 3.68 × 10−6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10−4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.

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Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

Cited by 52 publications

References 49 publications

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

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