A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals.

Autor: Lee YS; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Yu JE; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Kim KC; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Lee DH; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Son DJ; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Lee HP; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Jung JK; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Kim ND; Voronoibio Inc., Incheon, Korea., Ham YW; Department of Chemistry, Utah Valley University, Orem, UT, USA., Yun J; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Han SB; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea., Hong JT; College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2022 Jan; Vol. 16 (2), pp. 508-526. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1002/1878-0261.13138
Abstrakt: Our previous big data analyses showed a high level of association between chitinase 3 like1 (CHI3L1) expression and lung tumor development. In the present study, we investigated whether a CHI3L1-inhibiting chemical, 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284), could inhibit lung metastasis and studied its mechanism of action. We investigated the antitumor effect of K284 both in vitro and in vivo. K284 (0.5 mg·kg -1 body weight) significantly inhibited lung metastasis in in vivo models after injection of murine melanoma cells (B16F10) or adenocarcinomic human alveolar basal epithelial cells (A549). K284 significantly and concentration-dependently also inhibited cancer cell proliferation and migration in the A549 and H460 lung cancer cell lines. We found that the binding of K284 to the chitin-binding domain (CBD) of CHI3L1 prevented the binding of CHI3L1 to its receptor, interleukin-13 receptor subunit alpha-2 (IL-13Rα2), thereby suppressing the CHI3L1 signal. This blocking of the CHI3L1-IL-13Rα2 signal caused the inhibition of c-Jun N-terminal kinase (JNK)-activator protein 1 (AP-1) signals, resulting in the prevention of lung metastasis and cancer cell growth. Our data demonstrate that K284 may serve as a potential candidate anticancer compound targeting CHI3L1.
(© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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