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Updated: Jul 1, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis
Li Chen1,2,3, Wanzun Lin1,2,3, Haojiong Zhang1,2,3
1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China.
Abstract:
Tribbles pseudokinase 3 (TRIB3) has been identified recently as a novel oncogene in several cancers. Still, further extensive research is imperative to elucidate its function and the molecular mechanisms underlying its involvement in the progression of head and neck squamous cell carcinoma (HNSCC). In our study, we found that TRIB3 silencing significantly promoted cell death by inducing ferroptosis. The interaction of TRIB3 with Transcription Factor 4 (TCF4) and β-catenin created a heterotrimeric complex, which directly interacts with the ALOXE3 promoter, detrimentally impacting its activation. The consequential partial neutralization of ferroptosis induced by TRIB3 deficiency is observed through the implementation of ALOXE3 knockdown. Furthermore, the study demonstrated that the molecular inhibitor hesperidin, targeting TRIB3, not only reduced cell malignancy but also induced ferroptosis, thereby suppressing tumor growth. Overall, our findings unequivocally validate the proposition that TRIB3 deficiency precipitates the iron death mechanism, thereby indicating that the strategic targeting of TRIB3 could emerge as an innovative therapeutic strategy for HNSCC.
Insights
Tribbles pseudokinase 3 (TRIB3) promotes head and neck cancer by inhibiting ferroptosis. Targeting TRIB3 with hesperidin induces cell death and suppresses tumor growth, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tribbles pseudokinase 3 (TRIB3) is an emerging oncogene implicated in various cancers.
- Its precise role and molecular mechanisms in head and neck squamous cell carcinoma (HNSCC) progression require further investigation.
Purpose of the Study:
- To elucidate the function of TRIB3 in HNSCC.
- To investigate the molecular mechanisms by which TRIB3 influences cancer progression and ferroptosis.
- To evaluate TRIB3 as a potential therapeutic target in HNSCC.
Main Methods:
- TRIB3 silencing was performed to observe its effect on cancer cells.
- Interaction studies identified TRIB3's complex with Transcription Factor 4 (TCF4) and β-catenin.
- ALOXE3 promoter activity and knockdown were analyzed.
- The effect of hesperidin, a TRIB3 inhibitor, on cancer cells and tumor growth was assessed.
Main Results:
- TRIB3 silencing significantly induced cell death through ferroptosis.
- TRIB3 forms a complex with TCF4 and β-catenin, inhibiting ALOXE3 promoter activation.
- ALOXE3 knockdown partially rescued ferroptosis induced by TRIB3 deficiency.
- Hesperidin treatment reduced cancer cell malignancy, induced ferroptosis, and suppressed tumor growth.
Conclusions:
- TRIB3 deficiency triggers the ferroptosis mechanism in HNSCC.
- Targeting TRIB3 represents a promising therapeutic strategy for HNSCC treatment.
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