Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.,Acta Pharmacologica Sinica

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Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-07-08 , DOI: 10.1038/s41401-019-0260-6
Zeng-Li Zhang ₁ , Na-Na Wang ₂ , Qi-Lian Ma ₂ , Yang Chen ₂ , Li Yao ₂ , Li Zhang ₃ , Qiu-Shi Li ₄ , Min-Hua Shi ₁ , Hong-Feng Wang ₂ , Zheng Ying _{2,

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Affiliation

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.

中文翻译：

肿瘤抑制基因 PARK2 的体细胞和种系突变会损害 PINK1/Parkin 介导的肺癌细胞线粒体自噬。

PARK2 编码 Parkin，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发挥关键作用，PARK2 中的种系突变与帕金森病 (PD) 相关。有趣的是，最近的研究表明，Parkin 也可以作为一种肿瘤抑制因子，并且 PARK2 中的体细胞和种系突变与包括肺癌在内的各种人类癌症有关。然而，目前尚不清楚 Parkin 的肿瘤抑制活性如何受这些突变的影响，以及它是否与线粒体自噬有关。在这里，我们表明野生型 (WT) Parkin 可以在线粒体损伤后迅速转移到线粒体上，并且 Parkin 促进了肺癌细胞线粒体的线粒体清除。然而，肺癌相关突变抑制Parkin的线粒体易位和泛素相关活性。在我们测试的所有肺癌相关突变体中，A46T Parkin 未能转移到线粒体上，也不能招募下游线粒体调节剂，包括 optineurin (OPTN) 和 TFEB，而 N254S 和 R275W Parkin 的线粒体易位比 WT Parkin 慢。此外，我们发现去铁酮 (DFP)，一种可诱导线粒体自噬的铁螯合剂，大大增加了表达 A46T Parkin 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自噬机制，

更新日期：2019-07-08

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