Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells
Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells
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肿瘤抑制基因 PARK2 的体细胞和种系突变会损害肺癌细胞中 PINK1/Parkin 介导的线粒体自噬。
DOI：
10.1038/s41401-019-0260-6
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发表时间：
2019-07
影响因子：
8.2
通讯作者：
Ying Zheng
中科院分区：
文献类型：
--
作者：
Zhang Zeng-li;Wang Na-na;Ma Qi-lian;Chen Yang;Yao Li;Zhang Li;Li Qiu-shi;Shi Min-hua;Wang Hong-feng;Ying Zheng
编码Parkin的PARK2是神经退行性疾病和癌症的致病基因。Parkin可以作为一种神经保护剂，在线粒体自噬的调节中起着至关重要的作用，PARK2的种系突变与帕金森病（PD）有关。有趣的是，最近的研究表明，Parkin也可以作为肿瘤抑制因子，PARK2的体细胞和生殖细胞突变与各种人类癌症有关，包括肺癌。然而，目前尚不清楚帕金的肿瘤抑制活性如何受到这些突变的影响，以及它是否与线粒体自噬有关。在此，我们表明野生型（WT）帕金蛋白可以迅速易位到线粒体线粒体损伤后，帕金蛋白促进线粒体吞噬清除肺癌细胞中的线粒体。然而，肺癌相关突变抑制了线粒体易位和帕金蛋白的泛素相关活性。在我们测试的所有肺癌相关突变体中，A46 T Parkin未能易位到线粒体上，并且不能招募下游线粒体吞噬调节因子，包括视神经磷酸酶（OPTN）和TFEB，而N254 S和R275 W Parkin显示出比WT Parkin更慢的线粒体易位。此外，我们发现去铁酮（DFP），一种可以诱导线粒体自噬的铁螯合剂，大大增加了表达A46T帕金森蛋白的肺癌细胞的死亡。总之，我们的研究结果揭示了肺癌中一种新的线粒体吞噬机制，表明PARK2中肺癌相关突变与线粒体吞噬受损相关，并将DFP鉴定为PARK2相关肺癌和可能由线粒体吞噬失调驱动的其他类型癌症的新型治疗剂。
PARK2, which encodes Parkin, is a disease-causing gene for both neurodegenerative disorders and cancer. Parkin can function as a neuroprotector that plays a crucial role in the regulation of mitophagy, and germline mutations in PARK2 are associated with Parkinson’s disease (PD). Intriguingly, recent studies suggest that Parkin can also function as a tumor suppressor and that somatic and germline mutations in PARK2 are associated with various human cancers, including lung cancer. However, it is presently unknown how the tumor suppressor activity of Parkin is affected by these mutations and whether it is associated with mitophagy. Herein, we show that wild-type (WT) Parkin can rapidly translocate onto mitochondria following mitochondrial damage and that Parkin promotes mitophagic clearance of mitochondria in lung cancer cells. However, lung cancer-linked mutations inhibit the mitochondrial translocation and ubiquitin-associated activity of Parkin. Among all lung cancer-linked mutants that we tested, A46T Parkin failed to translocate onto mitochondria and could not recruit downstream mitophagic regulators, including optineurin (OPTN) and TFEB, whereas N254S and R275W Parkin displayed slower mitochondrial translocation than WT Parkin. Moreover, we found that deferiprone (DFP), an iron chelator that can induce mitophagy, greatly increased the death of A46T Parkin-expressing lung cancer cells. Taken together, our results reveal a novel mitophagic mechanism in lung cancer, suggesting that lung cancer-linked mutations in PARK2 are associated with impaired mitophagy and identifying DFP as a novel therapeutic agent for PARK2-linked lung cancer and possibly other types of cancers driven by mitophagic dysregulation.
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MicroRNA-26a/死亡相关蛋白激酶 1 信号传导诱导帕金森病中的突触核蛋白病和多巴胺能神经元变性
影响因子：
10.6
作者：
Su Y;Deng MF;Xiong W;Xie AJ;Guo J;Liang ZH;Hu B;Chen JG;Zhu X;Man HY;Lu Y;Liu D;Tang B;Zhu LQ
通讯作者：
Zhu LQ
DOI：
10.1042/bcj20160498
发表时间：
2017-04-13
期刊：
The Biochemical journal
影响因子：
--
作者：
Walden H;Muqit MM
通讯作者：
Muqit MM
影响因子：
64.5
作者：
Vyas S;Zaganjor E;Haigis MC
通讯作者：
Haigis MC
DOI：
10.1016/j.apsb.2016.06.005
发表时间：
2017-01
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Lv G;Sun D;Zhang J;Xie X;Wu X;Fang W;Tian J;Yan C;Wang H;Fu F
通讯作者：
Fu F
DOI：
10.1073/pnas.1113884108
发表时间：
2011-09-27
影响因子：
11.1
作者：
Zhang, Cen;Lin, Meihua;Feng, Zhaohui
通讯作者：
Feng, Zhaohui