Cell intrinsic role of COX-2 in pancreatic cancer development.
Cell intrinsic role of COX-2 in pancreatic cancer development.
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DOI：
10.1158/1535-7163.mct-12-0342
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发表时间：
2012-10
影响因子：
5.7
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Hill R;Li Y;Tran LM;Dry S;Calvopina JH;Garcia A;Kim C;Wang Y;Donahue TR;Herschman HR;Wu H
环氧化酶-2 （COX-2）在胰腺导管腺癌（PDAC）中表达上调。然而，COX-2如何促进PDAC的发展尚不清楚。虽然之前的研究已经通过使用非甾体抗炎药（NSAIDs）或COX-2抑制剂塞来昔布（celecoxib）在PDAC模型中评估了COX-2抑制的功效，但没有研究涉及COX-2在调节PDAC起始和进展中的细胞内在和微环境作用。我们使用功能丧失和功能获得两种方法测试了COX-2在PDAC进展中的细胞内在作用。在K-ras激活和Pten单倍不足的小鼠中，Pdx1+胰腺祖细胞中的Cox-2缺失显著延迟PDAC的发展。相反，在K-ras小鼠模型中，COX-2过表达促进PDAC的早期发病和进展。PTEN功能的丧失是决定PDAC致死性发病和总生存期的关键因素。机制上，COX-2过表达增加了Pdx1+、K-rasG12D/+；Ptenlox/+小鼠缺乏Pten LOH。相反，在相同环境下，Cox-2缺失会降低P-AKT水平并延缓癌症进展。这些数据表明，COX-2通过激活PI3K/AKT通路，在肿瘤的发生和发展中具有重要的细胞内在作用。不依赖内在COX-2表达的PDAC最终会随着FKBP5的减少和GRP78表达的增加而发展，这是导致AKT激活的两种替代途径。总之，这些结果支持COX-2在PDAC发展中的细胞内在作用，并表明，虽然抗COX-2治疗可能延迟PDAC的发展和进展，但已知的通过AKT激活增加化疗耐药的机制也必须克服。
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.