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SPINK5 promotes sensitivity to cisplatin by inducing ferroptosis in head and neck carcinoma
Hui Yao1, Guanghao Zhu1, Haopu Li1
1Department of Otolaryngology, Head and Neck Surgery, Shanghai Changhai Hospital, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
Abstract:
Cisplatin resistance remains a major obstacle in treating head and neck squamous cell carcinoma (HNSCC). Understanding its regulatory mechanisms is critical for improving therapeutic outcomes. SPINK5 expression was analyzed using TCGA datasets and tissue microarrays. Functional assays, including CCK-8, Annexin V-FITC/PI, and ferroptosis-specific probes (FerroOrange, DCFH-DA), were performed in SPINK5-overexpressing and FTH1-silenced HNSCC cells. Transcriptomic data were processed using R packages, with GSEA/GSVA for pathway analysis. Xenograft models were used to evaluate in vivo cisplatin responses. SPINK5 was significantly downregulated in HNSCC and correlated with poor prognosis and lymph node metastasis. Overexpression of SPINK5 enhanced cisplatin sensitivity by inducing ferroptosis, characterized by elevated ROS and Fe²⁺ levels, independent of classical apoptosis pathways. Unsupervised clustering and transcriptomic analysis identified FTH1 as a key downstream target of SPINK5. Mechanistically, SPINK5 suppressed FTH1 expression, promoting ferroptotic cell death and improving cisplatin efficacy in vitro and in vivo. SPINK5 functions as a tumor suppressor and sensitizes HNSCC cells to cisplatin by regulating ferroptosis via FTH1 downregulation, highlighting a novel therapeutic axis to overcome chemoresistance.
Insights
SPINK5 downregulation promotes cisplatin resistance in head and neck cancer. Restoring SPINK5 induces ferroptosis, enhancing chemotherapy effectiveness by targeting FTH1.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cisplatin resistance is a significant challenge in treating head and neck squamous cell carcinoma (HNSCC).
- Understanding the molecular mechanisms underlying cisplatin resistance is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of SPINK5 in HNSCC cisplatin resistance.
- To elucidate the mechanism by which SPINK5 influences chemoresistance, focusing on ferroptosis.
Main Methods:
- Analysis of SPINK5 expression in TCGA datasets and HNSCC tissues.
- In vitro functional assays (cell viability, apoptosis, ferroptosis) in HNSCC cell lines with altered SPINK5 and FTH1 levels.
- Transcriptomic analysis (GSEA/GSVA) and in vivo xenograft models to assess cisplatin response.
Main Results:
- SPINK5 was downregulated in HNSCC, correlating with poor prognosis and metastasis.
- SPINK5 overexpression sensitized HNSCC cells to cisplatin by inducing ferroptosis (elevated ROS and Fe²⁺), independent of apoptosis.
- FTH1 was identified as a direct downstream target of SPINK5, with SPINK5 suppressing FTH1 expression.
Conclusions:
- SPINK5 acts as a tumor suppressor in HNSCC.
- SPINK5 sensitizes HNSCC to cisplatin by inducing ferroptosis through FTH1 downregulation.
- Targeting the SPINK5-FTH1 axis offers a novel strategy to overcome cisplatin resistance in HNSCC.
