PT  - JOURNAL ARTICLE
AU  - Hill, Reginald
AU  - Li, Yunfeng
AU  - Tran, Linh M.
AU  - Dry, Sarah
AU  - Calvopina, Joseph Hargan
AU  - Garcia, Alejandro
AU  - Kim, Christine
AU  - Wang, Ying
AU  - Donahue, Timothy R.
AU  - Herschman, Harvey R.
AU  - Wu, Hong
TI  - Cell Intrinsic Role of COX-2 in Pancreatic Cancer Development
AID  - 10.1158/1535-7163.MCT-12-0342
DP  - 2012 Oct 01
TA  - Molecular Cancer Therapeutics
PG  - 2127--2137
VI  - 11
IP  - 10
4099  - http://mct.aacrjournals.org/content/11/10/2127.short
4100  - http://mct.aacrjournals.org/content/11/10/2127.full
SO  - Mol Cancer Ther2012 Oct 01; 11
AB  - 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 nonsteroidal anti-inflammatory drugs (NSAID) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic versus 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 overexpression 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 overexpression 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. Mol Cancer Ther; 11(10); 2127–37. ©2012 AACR.