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ERK-mediated NF-?B activation through ASIC1 in response to acidosis.

ABSTRACT: Acidic microenvironment is a common feature of solid tumors. We have previously shown that neuron specific acid-sensing ion channel 1 (ASIC1) is expressed in breast cancer, and it is responsible for acidosis-induced cellular signaling through AKT, leading to nuclear factor-?B (NF-?B) activation, and cell invasion and metastasis. However, AKT is frequently activated in cancer. Thus, a key question is whether ASIC1-mediated cell signaling still takes place in the cancer cells carrying constitutively active AKT. In the present study, we show that among four prostate cancer cell lines tested, 22Rv1 cells express the highest level of phosphorylated AKT that is not impacted by acidosis. However, acidosis can still induce NF-?B activation during which extracellular signal-regulated kinase (ERK) serves as an alternative pathway for ASIC-mediated cell signaling. Inhibition of ERK by chemical inhibitors or small interfering RNAs suppresses the acidosis-induced NF-?B activity through regulation of the inhibitory subunit I?B? phosphorylation. Furthermore, suppression of ASIC1-mediated generation of reactive oxygen species (ROS) by ROS scavengers, such as glutathione or N-acetyl-cysteine causes a decrease in ERK phosphorylation and degradation of I?B?. Finally, ASIC1 is upregulated in a subset of prostate cancer cases and ASIC1 knockout by CRISPR/Cas9 significantly suppresses cell invasion, and castration resistance both in vitro and in vivo. Together, these results support the significance of ASIC1-ROS-ERK-I?B?-NF-?B axis in prostate tumorigenesis, especially in the constitutively active AKT background.

SUBMITTER: Chen B

PROVIDER: S-EPMC5177778 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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ERK-mediated NF-κB activation through ASIC1 in response to acidosis.

Chen B B Liu J J Ho T-T TT Ding X X Mo Y-Y YY

Oncogenesis 20161212 12

Acidic microenvironment is a common feature of solid tumors. We have previously shown that neuron specific acid-sensing ion channel 1 (ASIC1) is expressed in breast cancer, and it is responsible for acidosis-induced cellular signaling through AKT, leading to nuclear factor-κB (NF-κB) activation, and cell invasion and metastasis. However, AKT is frequently activated in cancer. Thus, a key question is whether ASIC1-mediated cell signaling still takes place in the cancer cells carrying constitutive ...[more]

PMID: 27941930

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Project description:BACKGROUND:AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-?B is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS:The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-?B signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK ? catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-?B phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-?B signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-? and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-?B phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. CONCLUSIONS:AMPK activation modulates JNK-NF-?B signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.

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ERK-mediated NF-?B activation through ASIC1 in response to acidosis.

Publications

ERK-mediated NF-κB activation through ASIC1 in response to acidosis.

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