SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization
Jun Deng,
Xu Lin,
Jiajia Qin,
Qi Li,
Yingqiong Zhang,
Qingyi Zhang,
Cong Ji,
Shuying Shen,
Yangling Li,
Bo Zhang,
Nengming Lin
Affiliations
Jun Deng
Key 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
Xu Lin
Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
Jiajia Qin
Department of Pharmacy, The second Affiliated Hospital of Guangxi Medical University, GuangXi, 530007, China
Qi Li
Key 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
Yingqiong Zhang
Key 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
Qingyi Zhang
Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
Cong Ji
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
Shuying Shen
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
Yangling Li
Key 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
Bo Zhang
Key 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; Corresponding author.
Nengming Lin
Key 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; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Westlake University, Hangzhou, 310024, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China; Corresponding author. Key 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.
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.
