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Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma
Qiang Wang1, Handong Wang2, Yue Jia1
1Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China.
Objective:
Luteolin, a common dietary flavonoid, induces apoptosis of many types of cancer cells. However, its role in glioblastoma and the potential mechanisms remain unknown. In this research, we studied the molecular mechanisms of the anti-cancer effect of luteolin in glioblastoma cancer cell lines.
Methods:
Both U251MG and U87MG human glioblastoma cell lines were tested. Cell growth was assessed by the cell counting kit-8. Cell apoptosis was detected with flow cytometry and caspase-3 immunofluorescence staining. The protein levels of caspase-3/Bax/Bcl-2 and p-PERK/p-eIF2α/ATF4/CHOP/caspase-12 pathway were analyzed using western blots. Reactive oxygen species generation was measured with DCFH-DA staining using flow cytometry. Mitochondrial membrane potential was tested with JC-1 staining. Anti-cancer effect in vivo was measured using tumor xenograft mode in nude mice.
Results:
Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels. Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12. Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis. What's more, we also showed the anticancer effect of luteolin in vivo.
Conclusions:
Our results suggest that luteolin induces apoptosis through activating ER stress and mitochondrial dysfunction in glioblastoma cell lines and in vivo, which provides the anti-cancer candidate to treat glioblstoma.
Insights
Luteolin triggers cancer cell death in glioblastoma by causing endoplasmic reticulum stress and mitochondrial issues. This dietary compound shows promise as a potential glioblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Luteolin, a dietary flavonoid, exhibits anticancer properties against various cancer types.
- The specific mechanisms of luteolin's action in glioblastoma remain largely unexplored.
- Glioblastoma is an aggressive brain tumor with limited effective treatment options.
Purpose of the Study:
- To investigate the molecular mechanisms underlying luteolin's anti-cancer effects in glioblastoma cell lines.
- To determine if luteolin induces apoptosis in glioblastoma cells and elucidate the pathways involved.
- To evaluate the in vivo anti-cancer efficacy of luteolin in a glioblastoma xenograft model.
Main Methods:
- Utilized U251MG and U87MG human glioblastoma cell lines.
- Assessed cell viability, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial membrane potential.
- Analyzed key proteins in apoptosis and endoplasmic reticulum (ER) stress pathways via Western blotting.
- Evaluated in vivo anti-cancer effects using a tumor xenograft model in nude mice.
Main Results:
- Luteolin induced significant apoptosis in glioblastoma cells.
- Increased intracellular ROS levels were observed, triggering ER stress and mitochondrial dysfunction.
- Luteolin upregulated ER stress markers (p-PERK, p-eIF2α, ATF4, CHOP, cleaved-caspase-12) and apoptosis-related proteins (caspase-3, Bax/Bcl-2 ratio).
- Inhibition of ROS reversed luteolin-induced ER stress, mitochondrial dysfunction, and apoptosis.
- Luteolin demonstrated anti-cancer effects in vivo.
Conclusions:
- Luteolin induces glioblastoma cell apoptosis via ER stress activation and mitochondrial dysfunction.
- Increased ROS generation is a key mediator of luteolin's anti-cancer effects in glioblastoma.
- Luteolin presents a potential therapeutic candidate for glioblastoma treatment, supported by both in vitro and in vivo evidence.