IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway

Yang, Y.-F., Wang, Y.-Y., Hsiao, M., Lo, S. , Chang, Y.-C., Jan, Y.-H., Lai, T.-C., Lee, Y.-C., Hsieh, Y.-C. and Yuan, S.-S. F. (2020) IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway. Cancer Letters, 485, pp. 27-37. (doi: 10.1016/j.canlet.2020.04.025) (PMID:32417395)

Abstract

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.

• Item Type: Articles
• Keywords: ADORA1, AMP, IMPAD1, lung cancer, metabolism, tumor microenvironment.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hsieh, Dr Ya-Ching and Lo, Professor Steven
• Authors: Yang, Y.-F., Wang, Y.-Y., Hsiao, M., Lo, S., Chang, Y.-C., Jan, Y.-H., Lai, T.-C., Lee, Y.-C., Hsieh, Y.-C., and Yuan, S.-S. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Cancer Letters
• Publisher: Elsevier
• ISSN: 0304-3835
• ISSN (Online): 1872-7980
• Published Online: 15 May 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cancer Letters 485:27-37
• Publisher Policy: Reproduced under a Creative Commons licence