title: Regulation of breast tumorigenesis through acid sensors.
abstract: The low extracellular pH in the microenvironment has been shown to promote tumor growth and metastasis; however, the underlying mechanism is poorly understood. Particularly, little is known how the tumor cell senses the acidic signal to activate the acidosis-mediated signaling. In this study, we show that breast cancer cells express acid-sensing ion channel 1 (ASIC1), a proton-gated cation channel primarily expressed in the nervous system. RNA interference, knockout and rescue experiments demonstrate a critical role for ASIC1 in acidosis-induced reactive oxidative species and NF-κB activation, two key events for tumorigenesis. Mechanistically, ASIC1 is required for acidosis-mediated signaling through calcium influx. We show that as a cytoplasmic membrane protein, ASIC1 is also associated with mitochondria, suggesting that ASIC1 may regulate mitochondrial calcium influx. Importantly, interrogation of the Cancer Genome Atlas breast invasive carcinoma data set indicates that alterations of ASIC1 alone or combined with other 4 ASIC genes are significantly correlated with poor patient survival. Furthermore, ASIC1 inhibitors cause a significant reduction of tumor growth and tumor load. Together, these results suggest that ASIC1 contributes to breast cancer pathogenesis in response to acidic tumor microenvironments, and ASIC1 may serve as a prognostic marker and a therapeutic target for breast cancer.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Gupta
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: M
authors.initials: M
authors.lastname: Asters
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Pabbidi
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Mo
mesh_terms: D062565:Acid Sensing Ion Channels / Q000502:physiology*; D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium