Bupivacaine Induces Reactive Oxygen Species Production via Activation of the AMP-Activated Protein Kinase-Dependent Pathway

Pharmacology ◽  
2011 ◽  
Vol 87 (3-4) ◽  
pp. 121-129 ◽  
Author(s):  
Jun Lu ◽  
Shi Yuan Xu ◽  
Qing Guo Zhang ◽  
Hong Yi Lei
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Species Production ◽  
Amp Activated Protein Kinase ◽  
Dependent Pathway

scholarly journals Differential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells

2019 ◽  
Vol 294 (46) ◽  
pp. 17239-17248
Author(s):  
Karin Bartel ◽  
Rolf Müller ◽  
Karin von Schwarzenberg
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Reactive Oxygen Species Production ◽  
Differential Regulation ◽  
Oxygen Species ◽  
Atpase Inhibitors ◽  
Species Production ◽  
Amp Activated Protein Kinase ◽  
Atpase Inhibition

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and nontumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In nonmalignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a prosurvival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase–independent AMPK induction in tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a prosurvival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species production. We could attribute the prosurvival effects to AMPK's ability to maintain redox homeostasis by inhibiting reactive oxygen species production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.

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