3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms
2021
Аутори:
Kosić, MilicaPaunović, Verica
Ristić, Biljana
Mirčić, Aleksandar
Bošnjak, Mihajlo
Stevanović, Danijela
Kravić-Stevović, Tamara K
Trajković, Vladimir
Harhaji-Trajković, Ljubica
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.
Метаподаци
Приказ свих података о документуАпстракт:
We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone. 2DG/rotenone reduced ATP levels and increased mitochondrial superoxide production, causing mitochondrial swelling and necrotic death in various cancer cell lines. 2DG/rotenone failed to increase proautophagic beclin-1 and autophagic flux in melanoma cells despite the activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). 3MA, but not autophagy inhibition with other PI3K and lysosomal inhibitors, attenuated 2DG/rotenone-induced mitochondrial damage, oxidative stress, ATP depletion, and cell death, while antioxidant treatment mimicked its protective action. The protection was not mediated by autophagy upregulation via class I PI3K/Akt inhibition, as it was preserved in cells with genetically inhibited autophagy. 3MA increased AMPK and mTORC1 activation in energy-stressed cells, but neither AMPK nor mTORC1 inhibition reduced its cytoprotective effect. 3MA reduced JNK activation, and JNK pharmacological/genetic suppression mimicked its mitochondria-preserving and cytoprotective activity. Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.
Кључне речи:
3-Methyladenine; Glycolysis; Mitochondria; Autophagy; NecrosisИзвор:
Journal of Pharmacological Sciences, 2021, 147, 1, 156-167Финансирање / пројекти:
- UNESCO L'OREAL national scholarship program "For Women in Science", Grant No. 403F
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200110 (Универзитет у Београду, Медицински факултет) (RS-MESTD-inst-2020-200110)
DOI: 10.1016/j.jphs.2021.06.003
ISSN: 1347-8613
PubMed: 34294367
WoS: 000674666800021
Scopus: 2-s2.0-85109000842
URI
https://www.sciencedirect.com/science/article/pii/S1347861321000591https://radar.ibiss.bg.ac.rs/handle/123456789/4427