FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB

Cell & Bioscience

Research

Ji Su Lee¹  Ji Young Kim¹  Ji Hye Shin¹  Yeeun Kang¹  Mi-Jeong Kim¹  Juhee Son¹  Ki-Young Lee²  Duk-Hwan Kim³  Daesik Kim⁴  Eunyoung Chun⁵  Soo-Kyung Jeong⁵ 

[1] Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 16419, Suwon, Republic of Korea;Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 16419, Suwon, Republic of Korea;Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, 06351, Seoul, Republic of Korea;Single Cell Network Research Center, Sungkyunkwan University School of Medicine, 16419, Suwon, Republic of Korea;Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 16419, Suwon, Republic of Korea;Department of Precision Medicine, Sungkyunkwan University School of Medicine, 16419, Suwon, Republic of Korea;R&D Center, CHA Vaccine Institute, 13493, Seongnam-si, Republic of Korea;

关键词: FFAR2;    SCFAs;    Toll-like receptors;    NF-κB;    Lung cancer progression;   

DOI  :  10.1186/s13578-023-01038-y

 received in 2023-02-07, accepted in 2023-05-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundFree fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed.MethodsWe analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout (FFAR2KO) A549 and FFAR2KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation.ResultsThe clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2DownTLR2UpTLR3Up lung tumor tissues (LTTs) vs. FFAR2upTLR2DownTLR3Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2KO A549 and FFAR2KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines.ConclusionOur results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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