PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.
PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.
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DOI：
10.1038/s41388-020-1168-9
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发表时间：
2020-03
期刊：
影响因子：
8
通讯作者：
Warfel NA
中科院分区：
文献类型：
--
作者：
Chauhan SS;Toth RK;Jensen CC;Casillas AL;Kashatus DF;Warfel NA
化疗耐药性是非小细胞肺癌(NSCLC)成功治疗的主要障碍。这项研究的目的是确定PIM激酶如何影响肺癌患者的线粒体动力学、ROS产生和对化疗的反应。用活细胞成像和显微镜观察PIM缺失或抑制对线粒体表型和ROS的影响。抑制PIM激酶导致线粒体过度分裂和线粒体超氧化物歧化，增加细胞间ROS。从机制上讲，我们定义了一个连接PIM1和Drp1的信号轴，以及肺癌中线粒体的分裂。PIM抑制显著增加Drp1的蛋白水平和线粒体定位，导致线粒体明显碎裂。在非小细胞肺癌患者样本中，PIM1和Drp1之间存在负相关。抑制PIM可使NSCLC对化疗增敏，并在体内外产生协同抗肿瘤作用。免疫组织化学和透射电子显微镜证实，PIM抑制剂可促进体内线粒体的分裂和凋亡。这些数据提高了我们对PIM1如何调节线粒体的了解，并为在NSCLC中联合应用PIM抑制和化疗提供了理由。
Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intercellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC to chemotherapy and produced a synergistic anti-tumor response in vitro and in vivo. Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.
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影响因子：
8
作者：
通讯作者：
--
影响因子：
--
作者：
Song JH;Padi SK;Luevano LA;Minden MD;DeAngelo DJ;Hardiman G;Ball LE;Warfel NA;Kraft AS
通讯作者：
Kraft AS
天然产物川楝素逆转非小细胞肺癌对TRAIL的凋亡抗性
影响因子：
4.6
作者：
Li X;You M;Liu YJ;Ma L;Jin PP;Zhou R;Zhang ZX;Hua B;Ji XJ;Cheng XY;Yin F;Chen Y;Yin W
通讯作者：
Yin W
影响因子：
6
作者：
Roberts ER;Thomas KJ
通讯作者：
Thomas KJ
DOI：
10.3390/antiox7010013
发表时间：
2018-01-16
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ježek J;Cooper KF;Strich R
通讯作者：
Strich R