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

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

  • Chem Biol Interact. 2024 Aug 25:399:111143. doi: 10.1016/j.cbi.2024.111143.
Rajaghatta N Suresh 1,  Young Yun Jung 2,  Kachigere B Harsha 3,  Chakrabhavi Dhananjaya Mohan 4,  Kwang Seok Ahn 5,  Kanchugarakoppal S Rangappa 6
Affiliations

Affiliations

  • 1 Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
  • 2 Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdae-mun-gu, Seoul, 02447, Republic of Korea.
  • 3 Department of Chemistry, School of Engineering, University of Mysore, Mysuru, 570006, India.
  • 4 Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, Uttar Pradesh, India.
  • 5 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.
  • 6 Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India. Electronic address: rangappaks@ioe.uni-mysore.ac.in.
PMID: 39004389 DOI: 10.1016/j.cbi.2024.111143
Abstract

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.

Keywords

Apoptosis; Colon cancer; Isoxazolyl-urea; Paraptosis; Wnt/β-catenin.

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