Glutamate-mediated autophagy inhibition intensifies excitotoxic death of nutrient-deprived SH-SY5Y neuroblastoma cells
2019
Аутори:
Misirkić Marjanović, MajaVučićević, Ljubica
Ćirić, Darko
Martinović, Tamara
Jovanović, Maja
Isaković, Aleksandra
Marković, Ivanka
Trajković, Vladimir
Тип документа:
Конференцијски прилог (Објављена верзија)
,
© 2019 by the Nordic Autophagy Society
Метаподаци
Приказ свих података о документуАпстракт:
We investigated the role of autophagy in glutamate excitotoxicity during nutrient deprivation in vitro. Lack of serum, amino acids, and glucose markedly increased the sensitivity of SH-SY5Y human neuroblastoma cell line to glutamate-induced excitotoxic necrosis. Glutamate suppressed starvation-triggered autophagic response, as confirmed by diminished intracellular acidification, lower LC3 punctuation and conversion of LC3I to autophagosome associated LC3II, reduced levels of autophagy activators beclin-1 and ATG5, increased levels of the selective autophagic target NBR1, and reduced appearance of autophagic vesicles observed by transmission electron microscopy. Glutamate reduced starvation-triggered phosphorylation of the intracellular energy sensor AMP-activated protein kinase (AMPK), without affecting the activity of mammalian target of rapamycin complex1 as a major negative regulator of autophagy. Similar results were shown on PC12 cells, which are often exploited as a model for excitotoxicity. We also detected reduced mRNA expression of autophagy transcription factors FOXO3 and ATF4, as well as molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin 1, ATG5, ATG12), and the autophagy cargo delivery to autophagosmes (SQSTM1/p62). Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate dependent autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
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)
- Улога аутофагије у регулацији смрти туморских ћелија (RS-MESTD-Basic Research (BR or ON)-173053)
У:
- 3rd Nordic Autophagy Society (NAS) Conference; 2019 May 22-24; Utrecht, Netherlands. Nordic Autophagy Society; 2019. p. 34.