PUBLICATION
2-Methoxy-6-acetyl-7-methyljuglone (MAM) induced programmed necrosis in glioblastoma by targeting NAD(P)H: Quinone oxidoreductase 1 (NQO1)
- Authors
- Yu, J., Zhong, B., Jin, L., Hou, Y., Ai, N., Ge, W., Li, L., Liu, S., Lu, J.J., Chen, X.
- ID
- ZDB-PUB-200403-227
- Date
- 2020
- Source
- Free radical biology & medicine 152: 336-347 (Journal)
- Registered Authors
- Ai, Nana, Ge, Wei
- Keywords
- Glioblastoma, MAM, NQO1, Programmed necrosis
- MeSH Terms
-
- Animals
- Apoptosis
- Cell Line, Tumor
- Glioblastoma*/drug therapy
- Glioblastoma*/genetics
- Humans
- NAD
- NAD(P)H Dehydrogenase (Quinone)/genetics
- Naphthoquinones*/pharmacology
- Necrosis
- Zebrafish
- PubMed
- 32234332 Full text @ Free Radic. Biol. Med.
Citation
Yu, J., Zhong, B., Jin, L., Hou, Y., Ai, N., Ge, W., Li, L., Liu, S., Lu, J.J., Chen, X. (2020) 2-Methoxy-6-acetyl-7-methyljuglone (MAM) induced programmed necrosis in glioblastoma by targeting NAD(P)H: Quinone oxidoreductase 1 (NQO1). Free radical biology & medicine. 152:336-347.
Abstract
Glioblastoma (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. Temozolomide (TMZ), the only chemotherapeutic drug for GBM treatment, induced apoptosis but frequently developed resistance. Non-apoptotic cell death offers an alternative strategy to fight cancers. Our previous studies showed that 2-methoxy-6-acetyl-7-methyljuglone (MAM), a natural product, induced necroptosis in lung and colon cancer cells. The current study is designed to investigate its therapeutic potentials for GBM with in vitro and in vivo models. The protein expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in human GBM specimens were detected by immunohistochemistry. Effect of MAM on NQO1 was measured by recombinant protein and cellular thermal shift assay. The roles of NQO1 activation, superoxide (O2-2-) generation, calcium (Ca2+) accumulation, and c-Jun N-terminal kinase (JNK1/2) activation in MAM-induced cell death in U87 and U251 glioma cells were investigated. The effect of MAM on tumor growth was tested with a U251 tumor xenograft zebrafish model. Results showed that the NQO1 expression is positively correlated with the degree of malignancy in GBM tissues. MAM could directly bind and activate NQO1. Furthermore, MAM treatment induced rapid O2-2- generation, cytosolic Ca2+ accumulation, and sustained JNK1/2 activation. In addition, MAM significantly suppressed tumor growth in the zebrafish model. In conclusion, MAM induced GBM cell death by triggering an O2-2-/Ca2+/JNK1/2 dependent programmed necrosis. NQO1 might be the potential target for MAM and mediated its anticancer effect. This non-apoptotic necrosis might have therapeutic potentials for GBM treatment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping