Targeting KEAP1-mediated IKKβ degradation strategy for colitis-associated colorectal carcinogenesis: The potential of...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Colitis-associated colorectal cancer (CAC) involves the NF-κB pathway, particularly IKKβ, which promotes inflammation and cancer progression.
• Existing IKKβ inhibitors face challenges due to compensatory mechanisms, hindering clinical approval.
• There is a critical need for novel anti-tumor agents targeting IKKβ effectively while overcoming these compensatory pathways.

Purpose of the Study:

• To evaluate the anti-cancer effects of synthesized xanthohumol (XN) as a potential therapeutic agent targeting IKKβ in CAC.
• To investigate the molecular mechanisms by which XN inhibits IKKβ activity and signaling pathways.
• To explore the role of KEAP1 in IKKβ degradation and its interaction with XN.

Main Methods:

• In vitro and in vivo experiments using mouse models of CAC and human colon cancer cell lines.
• Histological and molecular analyses including cell viability assays, immunoblotting, and qRT-PCR.
• RNA sequencing to identify molecular targets and pathways, and molecular docking to determine binding sites.

Main Results:

• Elevated IKKβ expression in human colorectal cancer tissues correlated with poor prognosis.
• XN treatment significantly reduced adenocarcinoma formation and inflammation in vivo.
• XN inhibited IKKβ and NF-κB signaling, binding to IKKβ at C179 and KEAP1 at C288, promoting IKKβ degradation.

Conclusions:

• Xanthohumol (XN) demonstrates significant anti-cancer effects in colitis-associated colorectal cancer by targeting IKKβ.
• XN's mechanism involves direct inhibition of IKKβ and promotion of its degradation via KEAP1.
• XN represents a promising therapeutic candidate for colorectal cancer, addressing limitations of current IKKβ inhibitors.