P62-induced cancer-associated fibroblast activation via the Nrf2-ATF6 pathway promotes lung tumorigenesis

Cited 13 time in scopus
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Title
P62-induced cancer-associated fibroblast activation via the Nrf2-ATF6 pathway promotes lung tumorigenesis
Author(s)
Ji In Kang; Dong Hyun Kim; K W Sung; S M Shim; Hyunjoo Cha-MolstadNak-Kyun SoungKyung Ho LeeJoonsung HwangHee Gu Lee; Y T Kwon; Bo Yeon Kim
Bibliographic Citation
Cancers, vol. 13, no. 4, pp. 864-864
Publication Year
2021
Abstract
Cancer-associated fibroblasts (CAFs) are important in tumor progression. The autophagy adaptor protein, p62/SQSTM1/Sequestosome-1, is up-regulated in tumors, but down-regulated in CAFs in the early stages of lung adenocarcinoma. We investigated whether p62-induced autophagy might control CAF activation. Under CAF-inducing conditions, like hypoxia or cancer cell co-cultures, p62 ablation or autophagy inhibition with hydroxychloroquine (HCQ) impaired CAF activation and reduced transforming growth factor beta (TGFβ) production, which impeded tumor growth. During CAF activation, p62-induced autophagy up-regulated the expression of the anti-oxidant signaling protein, nuclear factor erythroid 2-related factor 2 (Nrf2), and the ER-stress response regulator, activating transcription factor 6 (ATF6). Genetically or pharmacologically inhibiting the Nrf2-ATF6 pathway totally blocked CAF activation and tumor progression. These results demonstrate that p62 is a key modulator of primary lung adenocarcinoma progression. Thus, targeting the p62-Nrf2 autophagy signaling pathway might be a novel, stroma-focused, cancer prevention and/or treatment strategy.
Keyword
Tumor microenvironmentCancer-associated fibroblastLung adenocarcinomap62/SQSTM1/Sequestosome-1Selective autophagyNuclear factor erythroid 2-related factor 2Activating transcription factor 6
ISSN
2072-6694
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/cancers13040864
Type
Article
Appears in Collections:
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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