AMPKα1 Regulates Lung and Breast Cancer Progression by Regulating TLR4-Mediated TRAF6-BECN1 Signaling Axis

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Abstract

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TRAF6-BECN1 signaling axis in TLR4 signal plays an essential role for the autophagy induction, thereby it regulates cancer migration and invasion. Here we show that AMPKα1, one of the isoforms of AMPK, is functionally involved in autophagy induction by regulating the TRAF6-BECN1 signaling axis. In this context, AMPKα1-knockout lung or breast cancer cells exhibited the attenuation of cancer cell migration and invasion induced by TLR4 simulation. Additionally, we could find that the expression of AMPKα1 is positively associated with gene expressions related to autophagy, migration, and metastasis of cancer cells in primary non-small cell lung cancers (NSCLCs). These findings demonstrate that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.

Abstract

TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 ( AMPKα1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPKα1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPKα1-knockout ( AMPKα1KO) HEK293T or AMPKα1-knockdown ( AMPKα1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPKα1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPKα1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPKαl levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs ( n = 5) with high AMPKαl levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPKα1KO MDA-MB-231 and AMPKα1KO MCF-7 human breast cancer cells. These results suggest that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.

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Most cited references 39

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Autophagy and the integrated stress response.

Guido Kroemer, Guillermo Mariño, Beth Levine (2010)

Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response. Copyright © 2010 Elsevier Inc. All rights reserved.

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Autophagy and autophagy-related proteins in cancer

Xiaohua Li, Shikun He, Binyun Ma (2020)

Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.

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Regulation mechanisms and signaling pathways of autophagy.

Congcong He, Daniel Klionsky (2009)

Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 06 November 2020

Publication date Collection: November 2020

Volume: 12

Issue: 11

Electronic Location Identifier: 3289

Affiliations

[1 ]Department of Immunology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Korea; kmjj0107@ 123456skku.edu (M.-J.K.); unizzzang@ 123456skku.edu (Y.M.); kimthsh@ 123456skku.edu (J.S.); bh9506@ 123456nate.com (J.Y.K.); alsdk0376@ 123456naver.com (J.S.L.)

[2 ]Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Korea; dukhwan@ 123456skku.edu

[3 ]Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Korea

[4 ]Samsung Medical Center, Seoul 06351, Korea

[5 ]Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea

Author notes

[* ]Correspondence: thylee@ 123456skku.edu ; Tel.: +82-31-299-6225

[†]

Authors contributed equally to this work.

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Ki-Young Lee https://orcid.org/0000-0002-6722-1751

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Publisher ID: cancers-12-03289

DOI: 10.3390/cancers12113289

PMC ID: 7694660

PubMed ID: 33172060

SO-VID: 9e2a00b7-666f-449e-a16e-3720737a0cc3

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

AMPKα1 Regulates Lung and Breast Cancer Progression by Regulating TLR4-Mediated TRAF6-BECN1 Signaling Axis

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Cancer Metabolism

Most cited references 39

Autophagy and the integrated stress response.

Autophagy and autophagy-related proteins in cancer

Regulation mechanisms and signaling pathways of autophagy.

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