Journal
ONCOTARGET
Volume 5, Issue 23, Pages 12070-12082Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2514
Keywords
Acidosis; AKT; NF-kappa B; Invasion; breast cancer; inflammation; ROS; tumor microenvironment
Categories
Funding
- National Institutes of Health [R01 CA154989]
- UMMC
- COBRE [GM103328]
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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-kappa B is a key factor for acidosis-induced cell invasion. Acidosis activates NF-kappa B without affecting STAT3 activity; knockdown of NF-kappa B p65 abrogates the acidosis-induced invasion activity. Next, we show that the activation of NF-kappa B is mediated through phosphorylation and degradation of I kappa B alpha; and phosphorylation and nuclear translocation of p65. Upstream to NF-kappa 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-kappa 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-kappa 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.
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