| Autor: |
Hill R; Corresponding Author: Hong Wu, Department of Molecular and Medical Pharmacology, CHS 33-131, 650 CE Young Drive South, Los Angeles, CA 90095, USA., Li Y, Tran LM, Dry S, Calvopina JH, Garcia A, Kim C, Wang Y, Donahue TR, Herschman HR, Wu H |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular cancer therapeutics [Mol Cancer Ther] 2012 Oct; Vol. 11 (10), pp. 2127-37. Date of Electronic Publication: 2012 Jul 10. |
| DOI: |
10.1158/1535-7163.MCT-12-0342 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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