We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells.
- Authors
Mochizuki, T.; Furuta, S.; Mitsushita, J.; Shang, W. H.; Ito, M.; Yokoo, Y.; Yamaura, M.; Ishizone, S.; Nakayama, J.; Konagai, A.; Hirose, K.; Kiyosawa, K.; Kamata, T.
- Abstract
Pancreatic adenocarcinoma is an aggressive human malignancy and is characterized by resistance to apoptosis. Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells. The signaling mechanism by which Nox4 transmits cell survival signals remains unclear. Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4RNAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis. Parallely, DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. Furthermore, AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser-83 was reduced by DPI and siNox4RNAs. When ASK1Ser83Ala (an AKT phosphorylation-defective ASK1 mutant) was introduced into PANC-1 cells, this mutant alone induced apoptosis. But, addition of DPI or co-transfection of siNox4RNA had no additive effect, indicating that the mutant can substitute for these reagents in apoptosis induction. Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT–ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis.Oncogene (2006) 25, 3699–3707. doi:10.1038/sj.onc.1209406; published online 13 March 2006
- Subjects
APOPTOSIS; CELL death; CANCER cells; PANCREAS; PHOSPHORYLATION; CHEMICAL reactions
- Publication
Oncogene, 2006, Vol 25, Issue 26, p3699
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209406