Angiotensin II regulates the expression of monocyte chemoattractant protein-1 in pancreatic cancer cells.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers with an overall median survival of less than 9 months and a 5-year survival rate of less than 5%. Increasing evidence indicates that inflammation facilitates PDA growth.


CONCLUSIONS
Angiotensin II (AngII), the principal hormone of the renin-angiotensin system, is actively generated in the pancreas and has been proposed as a key mediator of inflammation. Monocyte chemoattractant protein (MCP)-1 is a chemokine that plays an important role in the recruitment of mononuclear cells into sites of inflammation. In this study, we investigated the potential proinflammatory role of AngII in PDA through studying its effect on MCP-1. AngII significantly increased the expression of MCP-1 mRNA and protein in PDA cells and induced its promoter activity. Constitutive and AngII-induced MCP-1 transcription was inhibited by an AngII type 1 receptor (AT1R) blocker, but was unchanged by an AT2R blocker. AngII activated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, but not p38 or c-Jun NH2-terminal mitogen-activated protein kinases. Inhibition of ERK1/2 activation reduced the AngII-induced MCP-1 synthesis. AngII induced the activation and nuclear translocation of nuclear factor-kappaB (NF-kappaB), an effect that was inhibited by AT1R blockade. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate decreased the AngII-mediated increase in MCP-1 mRNA. Our data provide a novel insight into an AngII-initiated signal transduction pathway that regulates MCP-1 as a possible inflammatory mechanism in PDA and suggest that AngII blockade may regulate chemokine-induced signal transduction to prevent or reduce inflammation in PDA.
Chehl
Navdeep
N
Department of Surgery, Jefferson Pancreatic, Biliary & Related Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107, USA.
Gong
Qiaoke
Q
Chipitsyna
Galina
G
Aziz
Tamer
T
Yeo
Charles J
CJ
Arafat
Hwyda A
HA
D000230:Adenocarcinoma / Q000737:chemistry*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000032:analysis* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000737:chemistry*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018932:Chemokine CCL2; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D019808:Losartan