Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-?B 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-?B is a key factor for acidosis-induced cell invasion. Acidosis activates NF-?B without affecting STAT3 activity; knockdown of NF-?B p65 abrogates the acidosis-induced invasion activity. Next, we show that the activation of NF-?B is mediated through phosphorylation and degradation of I?B?; and phosphorylation and nuclear translocation of p65. Upstream to NF-?B 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-?B, 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-?B 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.

SUBMITTER: Gupta SC 

PROVIDER: S-EPMC4322981 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature