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Nedd9 Restrains Autophagy to Limit Growth of Early Stage Non-Small Cell Lung Cancer
Journal article   Open access   Peer reviewed

Nedd9 Restrains Autophagy to Limit Growth of Early Stage Non-Small Cell Lung Cancer

Alexander Y Deneka, Meghan C Kopp, Anna S Nikonova, Anna V Gaponova, Anna A Kiseleva, Harvey H Hensley, Douglas B Flieder, Ilya G Serebriiskii and Erica A Golemis
Cancer research (Chicago, Ill.), v 81(13), pp 3717-3726
01 Jul 2021
DOI: https://doi.org/10.1158/0008-5472.CAN-20-3626
PMID: 34006524
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/0008-5472.CAN-20-3626View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Adaptor Proteins, Signal Transducing - physiology AMP-Activated Protein Kinases - genetics AMP-Activated Protein Kinases - metabolism Animals Autophagy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Proliferation Disease Models, Animal Gene Expression Regulation, Neoplastic Humans Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice Mice, Inbred C57BL Mice, Knockout Prognosis Proto-Oncogene Proteins p21(ras) - physiology Survival Rate Tumor Cells, Cultured Tumor Suppressor Protein p53 - physiology
Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in and, with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on mutation and loss (mice), deletion of (mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of and tumors into the lungs of -wild-type and -null mice indicated the effect of loss was cell-autonomous. Tumors in mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. tumors contained high levels of active LKB1 and AMPK and increased autophagy compared with tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth. SIGNIFICANCE: This study demonstrates a novel role for the scaffolding protein NEDD9 in regulating LKB1-AMPK signaling in early stage non-small cell lung cancer, suppressing autophagy and tumor growth.

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15 citations in Web of Science
14 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Oncology
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