A Natural CHI3L1—Targeting Compound, Ebractenoid F, Inhibits Lung Cancer Cell Growth and Migration and Induces Apoptosis by Blocking CHI3L1/AKT Signals

Our previous big data analyses reported a strong association between CHI3L1 expression and lung tumor development. In this present study, we investigated whether a CHI3L1-inhibiting natural compound, ebractenoid F, inhibits lung cancer cell growth and migration and induces apoptosis. Ebractenoid F concentration-dependently (0, 17, 35, 70 µM) and significantly inhibited the proliferation and migration of A549 and H460 lung cancer cells and induced apoptosis. In the mechanism study, we found that ebractenoid F bound to CHI3L1 and suppressed CHI3L1-associated AKT signaling. Combined treatment with an AKT inhibitor, LY294002, and ebractenoid F synergistically decreased the expression of CHI3L1. Moreover, the combination treatment further inhibited the growth and migration of lung cancer cells and further induced apoptosis, as well as the expression levels of apoptosis-related proteins. Thus, our data demonstrate that ebractenoid F may serve as a potential anti-lung cancer compound targeting CHI3L1-associated AKT signaling.

[1]  J. Koo,et al.  CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses. , 2021, The Journal of clinical investigation.

[2]  J. Hong,et al.  Anti‐Chi3L1 antibody suppresses lung tumor growth and metastasis through inhibition of M2 polarization , 2021, Molecular oncology.

[3]  Huang Fang,et al.  M2a Macrophage-Secreted CHI3L1 Promotes Extracellular Matrix Metabolic Imbalances via Activation of IL-13Rα2/MAPK Pathway in Rat Intervertebral Disc Degeneration , 2021, Frontiers in Immunology.

[4]  J. Inazawa,et al.  Concurrent targeting of MAP3K3 and BRD4 by miR-3140-3p overcomes acquired resistance to BET inhibitors in neuroblastoma cells , 2021, Molecular therapy. Nucleic acids.

[5]  J. Hong,et al.  A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL‐13Rα2‐mediated JNK‐AP‐1 signals , 2021, Molecular oncology.

[6]  Xiaoren Zhang,et al.  Chitinase-3 like-protein-1 function and its role in diseases , 2020, Signal Transduction and Targeted Therapy.

[7]  Ji Young Kim,et al.  Decreased Lung Tumor Development in SwAPP Mice through the Downregulation of CHI3L1 and STAT 3 Activity via the Upregulation of miRNA342-3p , 2019, Molecular therapy. Nucleic acids.

[8]  Gabriela Bitencourt-Ferreira,et al.  Docking with SwissDock. , 2019, Methods in molecular biology.

[9]  S. Gurunathan,et al.  Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer , 2018, International journal of molecular sciences.

[10]  Yue Xu,et al.  Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer , 2018, Journal of Experimental & Clinical Cancer Research.

[11]  Ji Young Kim,et al.  Suppression of metastasis through inhibition of chitinase 3-like 1 expression by miR-125a-3p-mediated up-regulation of USF1 , 2018, Theranostics.

[12]  Mingshi Yang,et al.  Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[13]  Herman Yeger,et al.  Combination therapy in combating cancer , 2017, Oncotarget.

[14]  Y. Modis,et al.  IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses , 2016, Nature Communications.

[15]  J. Kzhyshkowska,et al.  Role of chitinase-like proteins in cancer , 2016, Biological chemistry.

[16]  Jiying Wang,et al.  Elevated Serum Concentration of Chitinase 3-Like 1 is an Independent Prognostic Biomarker for Poor Survival in Lung Cancer Patients , 2016, Cellular Physiology and Biochemistry.

[17]  J. Hong,et al.  Diterpenoids from the Roots of Euphorbia fischeriana with Inhibitory Effects on Nitric Oxide Production. , 2016, Journal of Natural Products.

[18]  J. Koo,et al.  Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis. , 2015, Cancer research.

[19]  R. Rosell,et al.  Lung cancer in 2014: Optimizing lung cancer treatment approaches , 2015, Nature Reviews Clinical Oncology.

[20]  Buqu Hu,et al.  Chitinase 3–Like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis , 2014, Science Translational Medicine.

[21]  Andrey Rzhetsky,et al.  DiseaseConnect: a comprehensive web server for mechanism-based disease–disease connections , 2014, Nucleic Acids Res..

[22]  Li Yu,et al.  Serum YKL-40 Level Is Associated with the Chemotherapy Response and Prognosis of Patients with Small Cell Lung Cancer , 2014, PloS one.

[23]  Feng Zhao,et al.  Anti-inflammatory diterpenoids from the roots of Euphorbia ebracteolata. , 2014, Journal of natural products.

[24]  R. Carrio,et al.  Exploring the role of CHI3L1 in “pre-metastatic” lungs of mammary tumor-bearing mice , 2013, Front. Physiol..

[25]  Xiao-jiang Hao,et al.  Two New Rosane‐Type Diterpenoids from Euphorbia ebracteolata Hayata , 2013 .

[26]  Y. Modis,et al.  Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2 , 2013, Cell reports.

[27]  Doron Lancet,et al.  MalaCards: an integrated compendium for diseases and their annotation , 2013, Database J. Biol. Databases Curation.

[28]  B. Ma,et al.  Chitinase-like proteins in lung injury, repair, and metastasis. , 2012, Proceedings of the American Thoracic Society.

[29]  D. V. van Aalten,et al.  Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. , 2012, The Biochemical journal.

[30]  V. Lladó,et al.  Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells. , 2011, Clinical immunology.

[31]  B. Ma,et al.  Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. , 2011, Annual review of physiology.

[32]  D. Xie,et al.  Overexpression of YKL-40 is an independent prognostic marker in gastric cancer. , 2009, Human pathology.

[33]  F. Coffman.  Chitinase 3-Like-1 (CHI3L1): A Putative Disease Marker at the Interface of Proteomics and Glycomics , 2008, Critical reviews in clinical laboratory sciences.

[34]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[35]  Kenneth J. Hillan,et al.  Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer , 2004, Nature Reviews Drug Discovery.