The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancer
The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancer
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DOI：
10.1186/1476-4598-7-5
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发表时间：
2008-01-11
期刊：
影响因子：
37.3
通讯作者：
Zagon, Ian S.
中科院分区：
文献类型：
--
作者：
Cheng, Fan;McLaughlin, Patricia J.;Zagon, Ian S.
背景：胰腺癌是美国第四大癌症死亡原因。S.阿片样生长因子（OGF; [Met（5）]-脑啡肽）和OGF受体形成参与胰腺癌发病机制和治疗的抑制性生长调节系统。OGF-OGFr轴影响细胞周期的G（0）/G（1）期。结果：在BxPC-3细胞中，OGF降低视网膜母细胞瘤（Rb）蛋白的磷酸化，而不改变总Rb。这种变化与细胞周期蛋白依赖性激酶蛋白（Cdk）2激酶活性降低相关，但与总Cdk 2无关。与对照组相比，OGF治疗增加了细胞周期蛋白依赖性激酶抑制剂（CKI）p21蛋白的表达，以及与Cdk 2复合的p21水平。纳洛酮可抑制OGF诱导的p21蛋白表达增加，提示其具有受体介导的活性。p21特异性siRNA阻断了OGF对BxPC-3、PANC-1和Capan-2细胞增殖的抑制作用;阴性对照siRNA转染的细胞p21表达无变化，因此受到OGF的抑制。这些数据首次揭示了OGF在人胰腺癌中的细胞增殖抑制作用的靶点是p21 CKI途径，扩大这些肿瘤的诊断和治疗策略。
Background: Pancreatic cancer is the 4th leading cause of death from cancer in the U. S. The opioid growth factor (OGF; [Met(5)]-enkephalin) and the OGF receptor form an inhibitory growth regulatory system involved in the pathogenesis and treatment of pancreatic cancer. The OGF-OGFr axis influences the G(0)/G(1) phase of the cell cycle. In this investigation, we elucidate the pathway of OGF in the cell cycle.Results: Using BxPC-3 cells, OGF decreased phosphorylation of retinoblastoma (Rb) protein without changing total Rb. This change was correlated with reduced cyclin-dependent kinase protein (Cdk) 2 kinase activity, but not total Cdk2. OGF treatment increased cyclin-dependent kinase inhibitor (CKI) p21 protein expression in comparison to controls, as well levels of p21 complexed with Cdk2. Naloxone abolished the increased expression of p21 protein by OGF, suggesting a receptor-mediated activity. p21 specific siRNAs blocked OGF's repressive action on proliferation in BxPC-3, PANC-1, and Capan-2 cells; cells transfected with negative control siRNA had no alteration in p21 expression, and therefore were inhibited by OGF.Conclusion: These data are the first to reveal that the target of cell proliferative inhibitory action of OGF in human pancreatic cancer is a p21 CKI pathway, expanding strategies for diagnosis and treatment of these neoplasias.