Other
11 Authors
- Kim C,
- Herschman HR,
- Li Y,
- Calvopina JH,
- Dry S,
- Wang Y,
- Tran LM,
- Garcia A,
- Wu H,
- Donahue TR,
- Hill R
| First Author | Hill R | Year | 2012 |
| Journal | Mol Cancer Ther | Volume | 11 |
| Issue | 10 | Pages | 2127-37 |
| PubMed ID | 22784710 | Mgi Jnum | J:208743 |
| Mgi Id | MGI:5564887 | Doi | 10.1158/1535-7163.MCT-12-0342 |
| Citation | Hill R, et al. (2012) Cell intrinsic role of COX-2 in pancreatic cancer development. Mol Cancer Ther 11(10):2127-37 |
| abstractText | 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-ras(G12D)(/+); Pten(lox)(/+) 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. |
