AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.
2019
Аутори:
Jovanović-Tucović, MajaHarhaji-Trajković, Ljubica
Dulović, Marija
Tovilović-Kovačević, Gordana
Zogović, Nevena
Jeremić, Marija
Mandić, Miloš
Kostić, Vladimir
Trajković, Vladimir
Marković, Ivanka
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier B.V.
Метаподаци
Приказ свих података о документуАпстракт:
We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.
Кључне речи:
AMPK; Akt; Autophagy; MPP+; Neurons; Oxidative stressИзвор:
European Journal of Pharmacology, 2019, 863, 172677-Финансирање / пројекти:
- Модулација сигналних путева који контролишу интрацелуларни енергетски баланс у терапији тумора и неуро-имуно-ендокриних поремећаја (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41025)
- Моторни и немоторни симптоми паркинсонизма: клиничке, морфолошке и молекуларно-генетичке корелације (RS-MESTD-Basic Research (BR or ON)-175090)
- Улога аутофагије у регулацији смрти туморских ћелија (RS-MESTD-Basic Research (BR or ON)-173053)
DOI: 10.1016/j.ejphar.2019.172677
ISSN: 0014-2999
PubMed: 31542478
WoS: 000491966400008
Scopus: 2-s2.0-85072619805
URI
https://www.sciencedirect.com/science/article/pii/S0014299919306296?via%3Dihubhttps://radar.ibiss.bg.ac.rs/handle/123456789/3482