Generation of Hydrogen Peroxide and Downstream Protein Kinase D1 Signaling Is a Common Feature of Inducers of Pancreatic Acinar-to-Ductal Metaplasia.
Generation of Hydrogen Peroxide and Downstream Protein Kinase D1 Signaling Is a Common Feature of Inducers of Pancreatic Acinar-to-Ductal Metaplasia.
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DOI：
10.3390/antiox11010137
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发表时间：
2022-01-08
期刊：
影响因子：
--
通讯作者：
Storz P
中科院分区：
文献类型：
--
作者：
Döppler HR;Liou GY;Storz P
胰腺腺泡至导管化生(ADM)是胰腺损伤后发生的可逆过程，但在KRAS、KRAS等癌基因突变存在的情况下成为永久性的，并导致胰腺病变。虽然炎性巨噬细胞分泌的趋化因子、激活表皮生长因子受体(EGFR)的生长因子和致癌的KRAS参与了ADM的诱导，但目前尚不清楚是否存在共同的潜在信号机制来驱动这一过程。在这项研究中，我们表明不同的ADM诱导剂增加了过氧化氢的水平，很可能是在线粒体产生的，并上调了蛋白激酶D1(PKD1)的表达，这是一种可以被过氧化氢激活的激酶。Kpd1在腺泡细胞中的表达影响其生存并介导多药耐药，这在一定程度上是由于pkd1靶向的核转录因子κB。总之，我们的数据提示ros-pkd1信号是不同胰腺多药诱导剂的共同特征。
Pancreatic acinar-to-ductal metaplasia (ADM) is a reversible process that occurs after pancreatic injury, but becomes permanent and leads to pancreatic lesions in the presence of an oncogenic mutation in KRAS,. While inflammatory macrophage-secreted chemokines, growth factors that activate epidermal growth factor receptor (EGFR) and oncogenic KRAS have been implicated in the induction of ADM, it is currently unclear whether a common underlying signaling mechanism exists that drives this process. In this study, we show that different inducers of ADM increase levels of hydrogen peroxide, most likely generated at the mitochondria, and upregulate the expression of Protein Kinase D1 (PKD1), a kinase that can be activated by hydrogen peroxide. PKD1 expression in acinar cells affects their survival and mediates ADM, which is in part due to the PKD1 target NF-κB. Overall, our data implicate ROS-PKD1 signaling as a common feature of different inducers of pancreatic ADM.
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