TY  - JOUR
AU  - Kosić, Milica
AU  - Paunović, Verica
AU  - Ristić, Biljana
AU  - Mirčić, Aleksandar
AU  - Bošnjak, Mihajlo
AU  - Stevanović, Danijela
AU  - Kravić-Stevović, Tamara K
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2021
UR  - https://www.sciencedirect.com/science/article/pii/S1347861321000591
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4427
AB  - 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.
PB  - Kyoto : Japanese Pharmacological Society
T2  - Journal of Pharmacological Sciences
T1  - 3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms
IS  - 1
VL  - 147
DO  - 10.1016/j.jphs.2021.06.003
SP  - 156
EP  - 167
ER  - 

@article{
author = "Kosić, Milica and Paunović, Verica and Ristić, Biljana and Mirčić, Aleksandar and Bošnjak, Mihajlo and Stevanović, Danijela and Kravić-Stevović, Tamara K and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2021",
abstract = "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.",
publisher = "Kyoto : Japanese Pharmacological Society",
journal = "Journal of Pharmacological Sciences",
title = "3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms",
number = "1",
volume = "147",
doi = "10.1016/j.jphs.2021.06.003",
pages = "156-167"
}

Kosić, M., Paunović, V., Ristić, B., Mirčić, A., Bošnjak, M., Stevanović, D., Kravić-Stevović, T. K., Trajković, V.,& Harhaji-Trajković, L.. (2021). 3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms. in Journal of Pharmacological Sciences
Kyoto : Japanese Pharmacological Society., 147(1), 156-167.
https://doi.org/10.1016/j.jphs.2021.06.003

Kosić M, Paunović V, Ristić B, Mirčić A, Bošnjak M, Stevanović D, Kravić-Stevović TK, Trajković V, Harhaji-Trajković L. 3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms. in Journal of Pharmacological Sciences. 2021;147(1):156-167.
doi:10.1016/j.jphs.2021.06.003 .

Kosić, Milica, Paunović, Verica, Ristić, Biljana, Mirčić, Aleksandar, Bošnjak, Mihajlo, Stevanović, Danijela, Kravić-Stevović, Tamara K, Trajković, Vladimir, Harhaji-Trajković, Ljubica, "3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms" in Journal of Pharmacological Sciences, 147, no. 1 (2021):156-167,
https://doi.org/10.1016/j.jphs.2021.06.003 . .