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SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization
Jun Deng1, Xu Lin2, Jiajia Qin3
1Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China; Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, GuangXi, 530021, China.
Abstract:
The function of SLC7A11 in the process of ferroptosis is well-established, as it regulates the synthesis of glutathione (GSH), thereby influencing tumor development along with drug resistance in non-small cell lung cancer (NSCLC). However, the determinants governing SLC7A11's membrane trafficking and localization remain unknown. Our study identified SPTBN2 as a ferroptosis suppressor, enhancing NSCLC cells resistance to ferroptosis inducers. Mechanistically, SPTBN2, through its CH domain, interacted with SLC7A11 and connected it with the motor protein Arp1, thus facilitating the membrane localization of SLC7A11 - a prerequisite for its role as System Xc-, which mediates cystine uptake and GSH synthesis. Consequently, SPTBN2 suppressed ferroptosis through preserving the functional activity of System Xc- on the membrane. Moreover, Inhibiting SPTBN2 increased the sensitivity of NSCLC cells to cisplatin through ferroptosis induction, both in vitro and in vivo. Using Abrine as a potential SPTBN2 inhibitor, its efficacy in promoting ferroptosis and sensitizing NSCLC cells to cisplatin was validated. Collectively, SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.
Insights
SPTBN2 suppresses ferroptosis in non-small cell lung cancer (NSCLC) by regulating SLC7A11 membrane localization. Inhibiting SPTBN2 enhances cisplatin sensitivity, offering a potential therapeutic strategy for NSCLC treatment.
Area of Science:
- Cell Biology
- Oncology
- Biochemistry
Background:
- Solute carrier family 7 member 11 (SLC7A11) is crucial for glutathione synthesis and ferroptosis, impacting non-small cell lung cancer (NSCLC) progression and drug resistance.
- The mechanisms controlling SLC7A11 membrane trafficking and localization are not fully understood.
Purpose of the Study:
- To identify novel regulators of SLC7A11 membrane localization and their role in ferroptosis and cisplatin resistance in NSCLC.
- To investigate the therapeutic potential of targeting SPTBN2 in NSCLC.
Main Methods:
- Immunofluorescence and co-immunoprecipitation assays to study protein interactions and localization.
- Cell viability assays and in vivo xenograft models to assess ferroptosis and drug sensitivity.
- Utilized Abrine as a potential SPTBN2 inhibitor.
Main Results:
- SPTBN2 was identified as a ferroptosis suppressor that enhances NSCLC cell resistance to ferroptosis inducers.
- SPTBN2 interacts with SLC7A11 via its CH domain, promoting its membrane localization and the function of System Xc-.
- Inhibition of SPTBN2, using Abrine, increased NSCLC cell sensitivity to cisplatin through ferroptosis induction both in vitro and in vivo.
Conclusions:
- SPTBN2 plays a critical role in regulating SLC7A11 membrane localization, thereby suppressing ferroptosis in NSCLC.
- Targeting SPTBN2 represents a promising therapeutic strategy to overcome cisplatin resistance in NSCLC by inducing ferroptosis.
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