Isoxazolyl-urea derivative evokes apoptosis and paraptosis by abrogating the Wnt/β-catenin axis in colon cancer cells.

Autor: Suresh RN; Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India., Jung YY; Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdae-mun-gu, Seoul, 02447, Republic of Korea., Harsha KB; Department of Chemistry, School of Engineering, University of Mysore, Mysuru, 570006, India., Mohan CD; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India., Ahn KS; Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdae-mun-gu, Seoul, 02447, Republic of Korea. Electronic address: ksahn@khu.ac.kr., Rangappa KS; Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India. Electronic address: rangappaks@ioe.uni-mysore.ac.in.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Aug 25; Vol. 399, pp. 111143. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1016/j.cbi.2024.111143
Abstrakt: Deregulated activation of the Wnt/β-catenin pathway is observed in many types of human malignancies including colon cancer. Abrogation of the Wnt/β-catenin pathway has been demonstrated as an effective way of inducing cancer cell death. Herein, a new isoxazolyl-urea (QR-5) was synthesized and examined its efficacy on the viability of colon cancer cell lines. QR-5 displayed selective cytotoxicity towards colon cancer cells over normal counterparts. QR-5 induced apoptosis as evidenced by elevation in sub-G1 cells, decrease in Bcl-2, MMP-9, COX-2, VEGF and cleavage of PARP and caspase-3. QR-5 reduced the mitochondrial membrane potential, decreased the expression of Alix and elevated the expression of ATF4 and CHOP indicating the induction of paraptosis. The inhibitor of apoptosis (Z-DEVD-FMK) and paraptosis (CHX) could not restore Alix expression and PARP cleavage in QR-5 treated cells, respectively suggesting the complementation between the two cell death pathways. QR-5 suppressed the expression of Wnt/β-catenin pathway proteins which was also evidenced by the downregulation of nuclear and cytoplasmic β-catenin. The dependency of QR-5 on β-catenin for inducing apoptosis and paraptosis was demonstrated by knockdown experiments using β-catenin specific siRNA. Overall, QR-5 induces apoptosis as well as paraptosis by mitigating the Wnt/β-catenin axis in colon cancer cells.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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