title: Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-κB pathway.
abstract: It is well known that acidic microenvironment promotes tumorigenesis, however, the underlying mechanism remains largely unknown. In the present study, we show that acidosis promotes invasiveness of breast cancer cells through a series of signaling events. First, our study indicates that NF-κB is a key factor for acidosis-induced cell invasion. Acidosis activates NF-κB without affecting STAT3 activity; knockdown of NF-κB p65 abrogates the acidosis-induced invasion activity. Next, we show that the activation of NF-κB is mediated through phosphorylation and degradation of IκBα; and phosphorylation and nuclear translocation of p65. Upstream to NF-κB signaling, AKT is activated under acidic conditions. Moreover, acidosis induces generation of reactive oxygen species (ROS) which can be suppressed by ROS scavengers, reversing the acidosis-induced activation of AKT and NF-κB, and invasiveness. As a negative regulator of AKT, PTEN is oxidized and inactivated by the acidosis-induced ROS. Finally, inhibition of NADPH oxidase (NOX) suppresses acidosis-induced ROS production, suggesting involvement of NOX in acidosis-induced signaling cascade. Of considerable interest, acidosis-induced ROS production and activation of AKT and NF-κB can be only detected in cancer cells, but not in non-malignant cells. Together, these results demonstrate a cancer specific acidosis-induced signaling cascade in breast cancer cells, leading to cell invasion.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Subash C
authors.initials: SC
authors.lastname: Gupta
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Radhika
authors.initials: R
authors.lastname: Pochampally
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Department of Microbiology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
mesh_terms: D000138:Acidosis / Q000150:complications*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051058:Oncogene Protein v-akt