Cell intrinsic role of COX-2 in pancreatic cancer development.
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.
Corresponding Author: Hong Wu, Department of Molecular and Medical Pharmacology, CHS 33-131, 650 CE Young Drive South, Los Angeles, CA 90095, USA.
Reginald
R
Hill
Yunfeng
Y
Li
Linh M
LM
Tran
Sarah
S
Dry
Joseph Hargan
JH
Calvopina
Alejandro
A
Garcia
Christine
C
Kim
Ying
Y
Wang
Timothy R
TR
Donahue
Harvey R
HR
Herschman
Hong
H
Wu
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D017353:Gene Deletion; D018390:Gene Targeting; D006360:Heat-Shock Proteins / Q000378:metabolism; D018398:Homeodomain Proteins; D019426:Integrases / Q000378:metabolism; D008017:Life Expectancy; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D016019:Survival Analysis; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D015534:Trans-Activators; D015854:Up-Regulation / Q000187:drug effects; D000099159:Tacrolimus Binding Protein 5
D000068579:Celecoxib; D051546:Cyclooxygenase 2; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; D019426:Integrases; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles; D013449:Sulfonamides; D022021:Tacrolimus Binding Proteins; D015534:Trans-Activators; D000099159:Tacrolimus Binding Protein 5; C000717248:Hspa5 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C077623:Ptgs2 protein, mouse; C045073:Cre recombinase; C495971:Hras protein, mouse