Aspirin Induced Glioma Apoptosis through Noxa Upregulation
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/12/4219 |
| _version_ | 1797565397391638528 |
|---|---|
| author | Cheng-Yi Chang Ping-Ho Pan Jian-Ri Li Yen-Chuan Ou Jiaan-Der Wang Su-Lan Liao Wen-Ying Chen Wen-Yi Wang Chun-Jung Chen |
| author_facet | Cheng-Yi Chang Ping-Ho Pan Jian-Ri Li Yen-Chuan Ou Jiaan-Der Wang Su-Lan Liao Wen-Ying Chen Wen-Yi Wang Chun-Jung Chen |
| author_sort | Cheng-Yi Chang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:12:34Z |
| format | Article |
| id | doaj.art-e9609adb17304586bbba486129e394e6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:12:34Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e9609adb17304586bbba486129e394e62023-11-20T03:44:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012112421910.3390/ijms21124219Aspirin Induced Glioma Apoptosis through Noxa UpregulationCheng-Yi Chang0Ping-Ho Pan1Jian-Ri Li2Yen-Chuan Ou3Jiaan-Der Wang4Su-Lan Liao5Wen-Ying Chen6Wen-Yi Wang7Chun-Jung Chen8Department of Surgery, Feng Yuan Hospital, Taichung City 420, TaiwanDepartment of Pediatrics, Tungs’ Taichung Metro Harbor Hospital, Taichung City 435, TaiwanDivision of Urology, Taichung Veterans General Hospital, Taichung City 407, TaiwanDepartment of Urology, Tungs’ Taichung Metro Harbor Hospital, Taichung City 435, TaiwanChildren’s Medical Center, Taichung Veterans General Hospital, Taichung City 407, TaiwanDepartment of Medical Research, Taichung Veterans General Hospital, Taichung City 407, TaiwanDepartment of Veterinary Medicine, National Chung Hsing University, Taichung City 402, TaiwanDepartment of Nursing, HungKuang University, Taichung City 433, TaiwanDepartment of Medical Research, Taichung Veterans General Hospital, Taichung City 407, TaiwanClinically, 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.https://www.mdpi.com/1422-0067/21/12/4219cyclooxygenaseER stressgliomaNSAID |
| spellingShingle | Cheng-Yi Chang Ping-Ho Pan Jian-Ri Li Yen-Chuan Ou Jiaan-Der Wang Su-Lan Liao Wen-Ying Chen Wen-Yi Wang Chun-Jung Chen Aspirin Induced Glioma Apoptosis through Noxa Upregulation International Journal of Molecular Sciences cyclooxygenase ER stress glioma NSAID |
| title | Aspirin Induced Glioma Apoptosis through Noxa Upregulation |
| title_full | Aspirin Induced Glioma Apoptosis through Noxa Upregulation |
| title_fullStr | Aspirin Induced Glioma Apoptosis through Noxa Upregulation |
| title_full_unstemmed | Aspirin Induced Glioma Apoptosis through Noxa Upregulation |
| title_short | Aspirin Induced Glioma Apoptosis through Noxa Upregulation |
| title_sort | aspirin induced glioma apoptosis through noxa upregulation |
| topic | cyclooxygenase ER stress glioma NSAID |
| url | https://www.mdpi.com/1422-0067/21/12/4219 |
| work_keys_str_mv | AT chengyichang aspirininducedgliomaapoptosisthroughnoxaupregulation AT pinghopan aspirininducedgliomaapoptosisthroughnoxaupregulation AT jianrili aspirininducedgliomaapoptosisthroughnoxaupregulation AT yenchuanou aspirininducedgliomaapoptosisthroughnoxaupregulation AT jiaanderwang aspirininducedgliomaapoptosisthroughnoxaupregulation AT sulanliao aspirininducedgliomaapoptosisthroughnoxaupregulation AT wenyingchen aspirininducedgliomaapoptosisthroughnoxaupregulation AT wenyiwang aspirininducedgliomaapoptosisthroughnoxaupregulation AT chunjungchen aspirininducedgliomaapoptosisthroughnoxaupregulation |