Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration

X Zheng; J Chi; J Zhi; H Zhang; D Yue; J Zhao; D Li; Y Li; M Gao; J Guo

doi:10.1038/onc.2017.354

Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration

Oncogene. 2018 Jan 25;37(4):502-511. doi: 10.1038/onc.2017.354. Epub 2017 Oct 2.

Authors

X Zheng¹, J Chi¹, J Zhi¹, H Zhang², D Yue³, J Zhao¹, D Li¹, Y Li¹, M Gao¹, J Guo⁴

Affiliations

¹ Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, China.
² Cancer Prevent Center, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, China.
³ Department of Lung Tumor, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, China.
⁴ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

PMID: 28967900
DOI: 10.1038/onc.2017.354

Abstract

Deletion or loss-of-function mutation of LKB1, frequently occurring in non-small cell lung cancers (NSCLCs), is a predominant caution of NSCLC initiation and progression. However, the upstream signaling pathways governing LKB1 activation are largely unknown. Here, we report that LKB1 undergoes Aurora kinase A (AURKA)-mediated phosphorylation, which largely compromises the LKB1/AMPK signaling axis, in turn leading to the elevation of NSCLC cell proliferation, invasion and migration. Mechanically, AURKA-mediated phosphorylation of LKB1 impairs LKB1 interaction with and phosphorylation of its downstream target AMPKα, which has critical roles in governing cancer cell energy metabolic homeostasis and tumorigenesis. Clinically, AURKA displays high levels in NSCLC patients, and correlates with poor outcome of patients with lung adenocarcinoma. Pathologically, the amplification or activation of AURKA-induced impairment of the LKB1/AMPK signaling pathway contributes to NSCLC initiation and progression, highlighting AURKA as a potential therapeutic target for combatting hyperactive AURKA-driven NSCLCs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases / metabolism*
Adenocarcinoma / genetics
Adenocarcinoma / mortality
Adenocarcinoma / pathology*
Adenocarcinoma of Lung
Aurora Kinase A / genetics
Aurora Kinase A / metabolism*
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinogenesis / pathology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / pathology*
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Computational Biology
Disease Progression
Enzyme Assays
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Lung / pathology
Lung Neoplasms / genetics
Lung Neoplasms / mortality
Lung Neoplasms / pathology*
Mutation
Neoplasm Invasiveness / pathology
Neoplasm Staging
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction / genetics
Tissue Array Analysis

Substances

Biomarkers, Tumor
AURKA protein, human
Aurora Kinase A
Protein Serine-Threonine Kinases
STK11 protein, human
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases