Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma

Abstract

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.

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