Compound 13, an α1-selective small molecule activator of AMPK, inhibits  Helicobacter pylori -induced oxidative stresses and gastric epithelial cell apoptosis

Zhao, Hangyong; Zhu, Huanghuang; Zhou, Lin; Lin, Gang; Lv, Guoqiang

doi:10.1016/j.bbrc.2015.05.059

Cited by 27 publications

(18 citation statements)

References 30 publications

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“…The AMPK activators AICAR and A769662 as well as the ER stress inhibitor salubrinal (Sal) [15] were obtained from Sigma (St. Louis, MO). Compound 13, a novel AMPK activator, was from Dr. Lv [16]. The pan-caspase inhibitor (z-VAD-fmk) and the specific caspase-12 inhibitor (z-ATAD-fmk) [17] were purchased from Calbiochem (Darmstadt, Germany).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells

Nie

Liu

Tan

et al. 2017

Biochemical and Biophysical Research Communications

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AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, its activity in human gallbladder cancer cells was evaluated here. We show that AICAR provoked significant apoptosis in human gallbladder cancer cell lines (Mz-ChA-1, QBC939 and GBC-SD) and primary gallbladder cancer cells. AICAR-induced cytotoxicity in gallbladder cancer cells appears independent of AMPK activation. Inhibition of AMPK, via AMPKα shRNA knockdown or dominant negative mutation (T172A), failed to rescue GBC-SD cells from AICAR. Further, forced-activation of AMPK, by adding two other AMPK activators (A769662 and Compound 13), or expressing a constitutively-active mutant AMPKα (T172D), didn't induce GBC-SD cell death. Remarkably, AICAR treatment in gallbladder cancer cells induced endoplasmic reticulum (ER) stress activation, the latter was tested by caspase-12 activation, C/EBP homologous protein (CHOP) expression and IRE1/PERK phosphorylation. Contrarily, salubrinal (the ER stress inhibitor), z-ATAD-fmk (the caspase-12 inhibitor) or CHOP shRNAs significantly attenuated AICAR-induced gallbladder cancer cell apoptosis. Together, we conclude that AICAR-induced gallbladder cancer cell apoptosis requires ER stress activation, but is independent of AMPK.

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Section: Chemicals and Reagentsmentioning

confidence: 99%

AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells

Nie

Liu

Tan

et al. 2017

Biochemical and Biophysical Research Communications

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“…Interestingly, PRKAA1 plays dual roles in carcinogenesis, both as a tumor suppressor that controls mTOR activation and as an oncogene involved in protection of cancer cell viability by maintaining NADPH and ATP levels under metabolic stress conditions [44][45][46]. Furthermore, AMPK is activated by HP infection in gastric epithelial cells, resulting in inhibition of ROS production and apoptosis in gastric epithelial cells [24,25]. These findings supported that interactions between PRKAA1 polymorphisms and HP infection play significant roles in gastric carcinogenesis, like presented in this study.…”

Section: Nod2)mentioning

confidence: 99%

Additive interactions between PRKAA1 polymorphisms and Helicobacter pylori CagA infection associated with gastric cancer risk in Koreans

et al. 2016

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Although several studies reported genetic polymorphisms in protein kinase AMP‐activated alpha 1 catalytic subunit (PRKAA1) and their associations with gastric cancer risk, few have evaluated associations between Helicobacter pylori infection and PRKAA1 gene‐environment interactions. Here, we evaluated the effects of interactions between H. pylori infection and PRKAA1 polymorphisms on gastric cancer risk in Koreans. In this hospital‐based case–control study, PRKAA1 genotypes were analyzed and H. pylori infection and CagA status were examined using a serologic method in 846 pairs of gastric cancer patients and controls matched for age and sex. H. pylori seropositivity was associated with a 1.43‐fold [95% confidence interval: 1.12–1.81] increase in the risk of gastric cancer, and CagA low‐positive titers during H. pylori infection increased the risk by 1.85‐fold (95% confidence interval, 1.38–2.48). Significant positive interaction between the PRKAA1 rs13361707 genotype and H. pylori infection was verified on an additive scale [relative excess risk due to interaction, 0.55; 95% confidence interval, 0.05–1.04; P = 0.030], and the gene‐environment interaction between PRKAA1 rs13361707 and CagA status was also statistically significant (relative excess risk due to interaction, 0.50; 95% confidence interval, 0.30–0.70; P < 0.001). Our results indicated that H. pylori infection, CagA status, and PRKAA1 polymorphisms were risk factors for gastric cancer in Koreans, and that the combination of two of these factors rather than their independent effects synergistically increased the risk.

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“…The decreased level of apoptosis originates persistence of infection and GEC proliferation, contributing to the development of carcinogenesis. Accordingly with these results, administration of compound 13, a novel α1-selective activator of AMPK, was shown to decrease H. pyloriinduced GEC apoptosis through reactive oxygen species (ROS) scavenging and activation of the AMPK-heme oxygenase (HO-1) pathway (Zhao et al 2015). Similarly, activation and overexpression of AMPK improve human brain microvascular endothelial cells (HBMECs) permeability after a challenge with lipopolysaccharide (LPS) through suppression of the induction of NAD(P)H oxidasederived ROS (Zhao et al 2014).…”

Section: Ampk In the Control Of Bacterial Infectionmentioning

confidence: 84%

AMPK in Pathogens

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Moreira

Sampaio‐Marques

et al. 2016

Experientia Supplementum

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During host-pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host-pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.

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Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori -induced oxidative stresses and gastric epithelial cell apoptosis

Cited by 27 publications

References 30 publications

AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells

AICAR activates ER stress-dependent apoptosis in gallbladder cancer cells

Additive interactions between PRKAA1 polymorphisms and Helicobacter pylori CagA infection associated with gastric cancer risk in Koreans

AMPK in Pathogens

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