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Precision Nutrition/Nutrient-Gene (Poster Session)

(P29-025-24) Identification of Phytochemical Formosanin C-induced Ferroptosis in Colorectal Cancer Through Bioinformatics Approaches

Monday, July 1, 2024
11:45 AM – 12:45 PM CT
Location: Poster Board 140

    Presenting Author(s)

  • CS

    Chun-Li Su, PhD

    Professor
    National Taiwan Normal University
    Taipei, Taipei, Taiwan (Republic of China)

    • Co-Author(s)

  • HC

    Hsin-Chih Chen

    National Taiwan Normal University, Taiwan (Republic of China)

  • CC

    Ching-Ying Chen

    National Taiwan Normal University, Taiwan (Republic of China)

Disclosure(s):
Chun-Li Su, PhD: No relevant financial relationship(s) with ineligible companies to disclose.


Objectives: Ferroptosis, a form of regulated cell death, is characterized by lipid peroxidation and is dependent on iron and reactive oxygen species (ROS). Drug-resistant cancer cells that persist after targeted therapy have been reported to be vulnerable to ferroptosis, thus potential phytochemicals that induce ferroptosis might expand the therapeutic armamentarium in oncology.

Methods: The mutated genes and prognosis of patients were obtained using GDC-TCGA and Kaplan-Meier Plotter databases. Differences in gene expressions were identified by the Xena platform. CLUE and ConsensusPathDB databases and Gene Set Enrichment Analyses were applied to discover potential phytochemicals.

Results: P53 and KRAS are the second and third most common frequently mutated genes and are associated with poor prognosis of patients with colorectal cancer (CRC). Differences in gene expressions between CRC and normal tissues indicate that CRC tends to have higher fatty acid and labile iron than normal tissue and thus is predisposed to ferroptosis, characterized by higher expressions of iron-regulating genes ACO1 (iron response protein 1), IREB2 (iron response protein 2) and TFRC (iron uptake) and lower expression of FTH1 (iron storage) as well as higher expression of antioxidation-regulating genes SLC7A11 (cystine uptake for glutathione biosynthesis) and ACSL4 (arachidonic acid and CoA combination catalysers). Through integrated analysis of differentially expressed genes and pathways, a diosgenin saponin formosanin C was predicted to act as a ferroptosis inducer in CRC by suppressing ROS detoxification gene NRF2. Indeed, formosanin C-induced lipid ROS formation and ferroptosis were observed. It is noteworthy that TP53 KD HCT 116 was less and KRAS overexpression HT-29 was more sensitive to formosanin C-induced ferroptosis compared to their corresponding parental counterparts. Moreover, formosanin C synergistically enhanced chemosensitivity to cisplatin, and this process was mediated by lipid ROS.

Conclusions: Ferroptosis is a targetable metabolic niche in CRC and formosanin C is an effective ferroptosis inducer in CRC cells with wild-type TP53 and oncogenic KRAS.

Funding Sources: The Ministry of Science and Technology, Taiwan and National Taiwan Normal University, Taiwan