Title: Cell Intrinsic role of Cox-2 in pancreatic cancer development
Organism(s): Mus musculus
Description: Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.
Design(s): transcription profiling by array
Experimental factor(s):
2 recorded
Pdx1-Cre+;PtenL/W;K-rasG12D/W,Cox-2 COE/W Pdx1-Cre+;PtenL/W;K-rasG12D/W,Cox-2 KO/KO
Publication(s): Hill R, Li Y, Tran LM, Dry S, Calvopina JH, Garcia A, Kim C, Wang Y, Donahue TR, Herschman HR, Wu H.
Cell intrinsic role of COX-2 in pancreatic cancer development. PubMed:22784710

Sample attribute(s):
Material Type
1 recorded
total RNA
cell line type
1 recorded
primary culture
strain background 1
1 recorded
2 recorded
Pdx1-Cre+;PtenL/W;K-rasG12D/W,Cox-2 COE/W Pdx1-Cre+;PtenL/W;K-rasG12D/W,Cox-2 KO/KO
1 recorded
older than 8 weeks
organism part
1 recorded
pancreatic tumor
1 recorded
affected gene
1 recorded
prostaglandin G/H synthase 2
strain background
1 recorded
1 recorded
Mus musculus
source tissue
1 recorded
pancreatic cancer cell
allele type
2 recorded
over expressed level knock out
Contact(s): Linh TranHong WuTimothy DonahueYunfeng LiYing WangSarah DryAlejandro GarciaJoseph CalvopinaHarvey HerschmanChristine KimReginald HillLinh Tran
Release Date: 6/28/2012
Submission Date:
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Assay Downloads
transcription profiling using DNA microarray
8 assays