The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation.
The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation.
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DOI：
10.1053/j.gastro.2011.10.026
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发表时间：
2012-02
期刊：
影响因子：
29.4
通讯作者：
Gukovskaya AS
中科院分区：
文献类型：
--
作者：
Nitsche C;Edderkaoui M;Moore RM;Eibl G;Kasahara N;Treger J;Grippo PJ;Mayerle J;Lerch MM;Gukovskaya AS
激酶Akt介导胰腺癌（PaCa）细胞对死亡的抗性，并且在癌细胞中具有组成性活性（磷酸化）。而激活Akt的激酶的特点是，少被称为磷酸酶，脱磷酸化，从而administerit.We研究调节Akt的活性和细胞死亡的磷酸酶PHLPP1和PHLPP2在PaCa细胞，小鼠模型PaCa，和人胰腺导管腺癌（PDAC）。我们测量了PHLPP过表达或用小干扰RNA敲低对Akt激活和细胞死亡的影响。我们研究了生长因子和活性氧对PHLPPs的调节，以及PHLPPs与肿瘤发生之间的关系。PHLPP过表达使Akt失活，而PHLPP敲低增加PaCa细胞中Akt的磷酸化。在人PDAC和PaCa的小鼠遗传和异种移植模型中，PHLPP的水平大大降低。PaCa细胞中PHLPP活性被生长因子和Nox 4还原的烟酰胺腺嘌呤二核苷酸磷酸氧化酶下调。PHLPP 1选择性地使Akt2去磷酸化，而PHLPP 2选择性地使Akt1去磷酸化。在PDAC中，Akt2而不是Akt1上调，Akt2水平与死亡率相关。与这些结果相一致，高水平的PHLPP 1（其使Akt2去磷酸化，而不是PHLPP 2，其使Akt1去磷酸化）与PDAC患者的较长生存时间相关。在小鼠中，来自过表达PHLPP 1（但不表达PHLPP 2）的PaCa细胞的异种移植肿瘤具有失活的Akt、更大程度的凋亡和更小的尺寸。PHLPP1具有肿瘤抑制活性，可能代表PDAC的治疗或诊断工具。
The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.