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A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals
Yong Sun Lee1, Ji Eun Yu1, Ki Cheon Kim1
1College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Korea.
Abstract:
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.
Insights
The novel compound K284 effectively inhibits lung metastasis and cancer cell growth by targeting chitinase 3 like 1 (CHI3L1). This CHI3L1 inhibitor blocks crucial signaling pathways, offering a potential new strategy for lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chitinase 3 like 1 (CHI3L1) expression is strongly associated with lung tumor development.
- Understanding the role of CHI3L1 in lung cancer progression is critical for developing targeted therapies.
Purpose of the Study:
- To investigate the efficacy of the CHI3L1-inhibiting chemical K284 in preventing lung metastasis.
- To elucidate the mechanism of action of K284 in inhibiting lung cancer growth and metastasis.
Main Methods:
- In vitro and in vivo studies were conducted using lung cancer cell lines (A549, H460) and animal models.
- The effect of K284 on cancer cell proliferation, migration, and lung metastasis was assessed.
- The molecular mechanism involving CHI3L1, its receptor IL-13Rα2, and downstream signaling pathways (JNK-AP-1) was investigated.
Main Results:
- K284 significantly inhibited lung metastasis in vivo at a dose of 0.5 mg·kg⁻¹ body weight.
- K284 demonstrated concentration-dependent inhibition of cancer cell proliferation and migration in A549 and H460 cells.
- K284 binds to the chitin-binding domain of CHI3L1, blocking its interaction with IL-13Rα2 and subsequently inhibiting JNK-AP-1 signaling.
Conclusions:
- K284 effectively suppresses lung metastasis and cancer cell growth by targeting the CHI3L1 pathway.
- The mechanism involves blocking the CHI3L1-IL-13Rα2 interaction and downstream JNK-AP-1 signaling.
- K284 shows potential as a candidate anticancer compound for lung cancer treatment targeting CHI3L1.
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