Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to...

Area of Science:

• Oncology
• Metabolomics
• Pharmacology

Background:

• Tumor microenvironments, particularly hypoxia and inflammation, significantly impact colorectal cancer (CRC) progression through altered polyamine metabolism.
• Identifying natural compounds that target these specific vulnerabilities is crucial for developing novel CRC therapies.

Purpose of the Study:

• To identify and characterize natural compounds that can effectively target metabolic vulnerabilities in colorectal cancer.
• To elucidate the mechanism of action of apigenin (API) in suppressing CRC progression.

Main Methods:

• Integrated untargeted metabolomics, network pharmacology, and a human endogenous metabolite library screen to identify API as an anti-CRC candidate.
• Utilized in vitro cell line studies (RKO, HCT116) and in vivo xenograft models to assess API's efficacy.
• Investigated the molecular mechanisms involving the HIF-1α/SMOX and TLR4/MyD88 pathways.

Main Results:

• Apigenin (API) significantly inhibited CRC cell proliferation, migration, and invasion in vitro and suppressed tumor growth in vivo.
• API dismantled a novel HIF-1α/SMOX positive feedback loop, reducing the spermidine/spermine ratio and inflammatory signaling.
• Polyamines were found to rescue CRC cells from API-induced cytotoxicity, highlighting their role in the therapeutic resistance.

Conclusions:

• Apigenin (API) represents a potent therapeutic candidate for colorectal cancer by targeting and disrupting the HIF-1α/SMOX and TLR4/MyD88-mediated inflammatory axis.
• API effectively remodels polyamine metabolism and suppresses CRC progression through a novel metabolic mechanism.
• Disruption of this metabolic axis offers a new therapeutic strategy for CRC treatment.