Abstract
Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma. To extend the current understanding of the apoptotic potential of aspirin in most cell types, this study provides evidence showing that aspirin induced glioma cell apoptosis and inhibited tumor growth, in vitro and in vivo. We found that the human H4 glioma cell-killing effects of aspirin involved mitochondria-mediated apoptosis accompanied by endoplasmic reticulum (ER) stress, Noxa upregulation, Mcl-1 downregulation, Bax mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. Genetic silencing of Noxa or Bax attenuated aspirin-induced viability loss and apoptosis, while silencing Mcl-1 augmented the effects of aspirin. Data from genetic and pharmacological studies revealed that the axis of ER stress comprised an apoptotic cascade leading to Noxa upregulation and apoptosis. The apoptotic programs and mediators triggered by aspirin in H4 cells were duplicated in human U87 glioma cell line as well as in tumor-bearing BALB/c nude mice. The involvement of ER stress in indomethacin-induced Mcl-1 downregulation was reported in our previous study on glioma cells. Therefore, the aforementioned phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis.
Highlights
Cyclooxygenase (COX) is a rate-limiting enzyme involved in the synthesis of eicosanoids from membrane-released arachidonic acid
I(nFti.gJ.uMreol.3SEci). 2a0n20d, 2c1a,sxpFaOsReP3EaERctRivEiVtyIEW(Figure 3F) occurred in Noxa-silenced but not Bim-silenced5coefl1l5s (Figure 3C). These findings indicate that Noxa plays a crucial role in delivering apoptotic signals caused Bbyima-sspilierninceadndceMllscl(-F1ihgausrean3Can).taTghoensiezifningdeiffngecst.indicate that Noxa plays a crucial role in delivering apoptotic signals caused by aspirin and Mcl-1 has an antagonizing effect
The findings of the pharmacological and genetic studies highlighted the activation of Bax and its contribution to aspirin-induced glioma cell apoptosis
Summary
Cyclooxygenase (COX) is a rate-limiting enzyme involved in the synthesis of eicosanoids from membrane-released arachidonic acid. The inducible COX-2 isozyme correlates well with cell proliferation, migration, invasion, angiogenesis, and anti-apoptosis [2,3]. Increased expression of anti-apoptotic Bcl-2 family proteins and/or decreased expression of pro-apoptotic members have been demonstrated in patients with malignant glioma, revealing a crucial role of apoptosis resistance in drug resistance, poor prognosis, and recurrence [16,17,18]. Nonselective COX inhibitor aspirin induces apoptosis in most cancer cells involving Mcl-1 downregulation [19,26,27,28,29]. To extend our understanding of the effects of aspirin on glioma apoptosis, the molecular bases of crosstalk between anti-apoptotic and pro-apoptotic Bcl-2 family proteins and underlying apoptotic programs were investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
