NADPH oxidase activation in pancreatic cancer cells is mediated through Akt-dependent up-regulation of p22phox.
We recently showed that Nox4 NADPH oxidase is highly expressed in pancreatic ductal adenocarcinoma and that it is activated by growth factors and plays a pro-survival, anti-apoptotic role. Here we investigate the mechanisms through which insulin-like growth factor I and serum (FBS) activate NADPH oxidase in pancreatic cancer (PaCa) cells. We show that in PaCa cells, NADPH oxidase is composed of Nox4 and p22(phox) catalytic subunits, which are both required for NADPH oxidase activity. Insulin-like growth factor I and FBS activate NADPH oxidase through transcriptional up-regulation of p22(phox). This involves activation of the transcription factor NF-κB mediated by Akt kinase. Up-regulation of p22(phox) by the growth factors results in increased Nox4-p22(phox) complex formation and activation of NADPH oxidase. This mechanism is different from that for receptor-induced activation of phagocytic NADPH oxidase, which is mediated by phosphorylation of its regulatory subunits. Up-regulation of p22(phox) represents a novel pro-survival mechanism through which growth factors and Akt inhibit apoptosis in PaCa cells.
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073.
Mouad
M
Edderkaoui
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073.
Claudia
C
Nitsche
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073.
Ling
L
Zheng
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073.
Stephen J
SJ
Pandol
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073.
Ilya
I
Gukovsky
From the Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, California 90073. Electronic address: agukovsk@ucla.edu.
Anna S
AS
Gukovskaya
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D016328:NF-kappa B; D007334:Insulin-Like Growth Factor I; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C086986:CYBA protein, human; D051057:Proto-Oncogene Proteins c-akt