ASIC1 inhibition impairs the proliferation and migration of pancreatic stellate cells induced by pancreatic cancer cells

Abstract

Activated pancreatic stellate cells (PSCs) with an increased proliferation and migration ability are the partners in crime with pancreatic cancer cells. Acid-sensing ion channel 1 (ASIC1) is expressed in pancreatic cancer and PSCs, and especially, it mediates the activation of PSCs. However, whether ASIC1 is involved in pancreatic cancer cells-induced biological behavior re-educating of PSCs is unclear. In this study, the change of ASIC1 expression in PSCs and pancreatic cancer Panc-1 cells after indirect co-culture was detected by western blotting, and the proliferation and migration of PSCs with ASIC1 knockdown under Panc-1 cells-conditioned medium (Panc-1-CM) was assessed. The results showed that pancreatic cancer cells induced ASIC1 overexpression, and the enhanced proliferation and migration of PSCs was weakened by ASIC1 inhibition. In addition, the extracellular signal-regulated kinase (ERK) expression in PSCs remained stable, but the phosphorylated ERK (p-ERK) expression in PSCs treated with Panc-1-CM increased, which was suppressed by ASIC1 knockdown. These results indicate that ASIC1 participates in the regulation of PSCs proliferation and migration induced by cancer cells via the ERK pathway, and ASIC1 inhibition may be beneficial to pancreatic cancer treatment.

Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension

“…The current findings that ASIC1a contributes to hypoxia-induced PASMC proliferation and migration support a direct contribution of ASIC1a to vascular remodeling. These data corroborate several studies showing that ASIC1, expressed in a variety of cancers, plays a role in regulating multiple malignant processes including proliferation, migration, epithelial-mesenchymal transition, and cell cycle progression ( Kapoor et al, 2009 ; Rooj et al, 2012 ; Jin et al, 2015 ; Wu et al, 2017 ; Zhu et al, 2017 ; Chen et al, 2018 ; Ding et al, 2021 ; Zhu et al, 2021 ). Conversely, prevention of right ventricular hypertrophy following deletion of SM- Asic1a suggests cardiomyocyte remodeling in this mouse model of hypoxic pulmonary hypertension largely occurs due to the role of ASIC1a to increase pulmonary vascular resistance.…”

Acid-Sensing Ion Channel 1/Calpain1 Activation Impedes Macrophage ATP-Binding Cassette Protein A1-Mediated Cholesterol Efflux Induced by Extracellular Acidification

“…Therefore, activation of ASIC1 enhances calcium influx and initiates intracellular signaling to trigger downstream events, such as inflammation and cell death ( Wang and Xu, 2011 ; Zhang R. J. et al, 2020 ). ASIC1 plays crucial roles in physiological and pathophysiological processes, including vascular remodeling, cognitive function disorders, pancreatic cancer, and cerebral ischemic injury ( Detweiler et al, 2019 ; Zhou et al, 2019 ; Zhu et al, 2021 ). Recently, Ni et al (2018) reported that ASIC1 activation results in macrophage cell inflammatory response, which impedes ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux from the cells.…”

Signaling Pathways in Proton and Non-proton ASIC1a Activation

“…As an example, the activation of ERK via ASIC1a (downstream ASIC1a activation) has been analyzed in different pathological conditions (Chen et al, 2016;Sun et al, 2018;Zhu et al, 2020Zhu et al, , 2021. In addition, this pathway has also been linked to inflammation (Yu et al, 2015).…”