4.7 Article

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

Journal

Publisher

MDPI
DOI: 10.3390/ijms21124219

Keywords

cyclooxygenase; ER stress; glioma; NSAID

Funding

  1. Central Region Hospital Alliance (Ministry of Health and Welfare, Taiwan)
  2. Feng Yuan Hospital
  3. Taichung Veterans General Hospital
  4. HungKuang University [TCVGH-HK1008004, 1018002]
  5. Ministry of Science and Technology [MOST 105-2628-B-668-001-MY3, 108-2314-B-668-001-MY2]

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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.

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