Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels.
Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels.
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DOI：
10.3389/fphys.2013.00246
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发表时间：
2013-09-12
影响因子：
4
通讯作者：
Michalski CW
中科院分区：
文献类型：
--
作者：
Kong B;Qia C;Erkan M;Kleeff J;Michalski CW
胰腺导管腺癌（PDAC）是一种毁灭性的疾病，没有明确的病因。最近的流行病学和动物研究表明，补充膳食抗氧化剂（例如，维生素C和E）降低癌症风险，这意味着活性氧（ROS）的增加可能在胰腺癌发生中起作用。然而，致癌Kras突变（例如，KrasG12D），其存在于超过90%的PDAC中，已被证明促进低细胞内ROS水平。在这里，致癌Kras通过Nrf2（核因子，红细胞衍生2，like 2）激活一系列抗氧化基因的表达，并且还介导谷氨酰胺的不寻常的代谢途径以产生NADPH。然后，这可以用作ROS解毒的还原能力，从而共同导致胰腺癌前细胞和癌细胞中的低ROS水平。在成体干细胞和癌症干细胞中，低ROS水平与允许增殖的细胞内环境的形成和自我更新能力的持久性有关。因此，可以想象，低细胞内ROS水平可能显著促进致癌Kras介导的PDAC形成。
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease without clearly known disease causes. Recent epidemiological and animal studies suggest that the supplementation of dietary antioxidants (e.g., vitamins C and E) decreases cancer risk, implying that increased reactive oxygen species (ROS) may play a role in pancreatic carcinogenesis. However, oncogenic Kras mutations (e.g., KrasG12D), which are present in more than 90% of PDAC, have been proven to foster low intracellular ROS levels. Here, oncogenic Kras activates expression of a series of anti-oxidant genes via Nrf2 (nuclear factor, erythroid derived 2, like 2) and also mediates an unusual metabolic pathway of glutamine to generate NADPH. This can then be used as the reducing power for ROS detoxification, leading collectively to low ROS levels in pancreatic pre-neoplastic cells and in cancer cells. In adult stem cells and cancer stem cells, low ROS levels have been associated with the formation of a proliferation-permissive intracellular environment and with perseverance of self-renewal capacities. Therefore, it is conceivable that low intracellular ROS levels may contribute significantly to oncogenic Kras-mediated PDAC formation.
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