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IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway.
Cancer Letters ( IF 9.1 ) Pub Date : 2020-05-14 , DOI: 10.1016/j.canlet.2020.04.025
Yi-Fang Yang , Yen-Yun Wang , Michael Hsiao , Steven Lo , Yu-Chan Chang , Yi-Hua Jan , Tsung-Ching Lai , Yi-Chen Lee , Ya-Ching Hsieh , Shyng-Shiou F. Yuan

The tumor microenvironment (TME) and metabolic reprogramming have been implicated in cancer development and progression. However, the link between TME, metabolism, and cancer progression in lung cancer is unclear. In the present study, we identified IMPAD1 from the conditioned medium of highly invasive CL1-5. High expression of IMPAD1 was associated with a poorer clinical phenotype in lung cancer patients, with reduced survival and increased lymph node metastasis. Knockdown of IMPAD1 significantly inhibited migration/invasion abilities and metastasis in vitro and in vivo. Upregulation of IMPAD1 and subsequent accumulation of AMP in cells increased the pAMPK, leading to Notch1 and HEY1 upregulation. As AMP is an ADORA1 agonist, treatment with ADORA1 inhibitor reduced the expression of pAMPK and HEY1 expression in IMPAD1-overexpressing cells. IMPAD1 caused mitochondria dysfunction by inhibiting mitochondrial Complex I activity, which reduced mitochondrial ROS levels and activated the AMPK-HEY1 pathway. Collectively this study supports the multipotent role of IMPAD1 in promotion of lung cancer metastasis by simultaneously increasing AMP levels, inhibition of Complex I activity to decrease ROS levels, thereby activating AMPK-Notch1-HEY1 signaling, and providing an alternative metabolic pathway in energy stress conditions.

中文翻译:

IMPAD1充当线粒体电子转运抑制剂,可防止ROS产生并通过AMPK-Notch1-HEY1途径促进肺癌转移。

肿瘤微环境(TME)和代谢重编程已牵涉到癌症的发展和进程。但是,肺癌中TME,代谢和癌症进展之间的联系尚不清楚。在本研究中,我们从高侵袭性CL1-5的条件培养基中鉴定了IMPAD1。IMPAD1的高表达与肺癌患者较差的临床表型有关,生存率降低且淋巴结转移增加。敲除IMPAD1会在体内外显着抑制迁移/侵袭能力和转移。IMPAD1的上调和随后AMP在细胞中的积累增加了pAMPK,导致Notch1和HEY1上调。由于AMP是ADORA1激动剂,因此用ADORA1抑制剂处理可降低IMPAD1过表达细胞中pAMPK的表达和HEY1的表达。IMPAD1通过抑制线粒体复合体I活性而导致线粒体功能障碍,从而降低线粒体ROS水平并激活AMPK-HEY1途径。这项研究总体上支持IMPAD1在促进肺癌转移中的多能作用,方法是同时提高AMP水平,抑制Complex I活性以降低ROS水平,从而激活AMPK-Notch1-HEY1信号传导,并在能量压力条件下提供另一种代谢途径。
更新日期:2020-05-15
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