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 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-κB 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-κB activity through regulation of the inhibitory subunit IκBα 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 IκBα. 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-IκBα-NF-κB axis in prostate
tumorigenesis, especially in the constitutively active AKT background.