Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells

Lixin He; Jinxin Chen; Pinwei Deng; Shumei Huang; Pian Liu; Chanjuan Wang; Xinjian Huang; Yue Li; Boyu Chen; Dongni Shi; Yunyun Xiao; Xiangfu Chen; Ying Ouyang; Libing Song; Chuyong Lin

doi:10.1016/j.molcel.2023.08.032

Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells

Mol Cell. 2023 Oct 5;83(19):3502-3519.e11. doi: 10.1016/j.molcel.2023.08.032. Epub 2023 Sep 25.

Authors

Lixin He¹, Jinxin Chen¹, Pinwei Deng¹, Shumei Huang², Pian Liu³, Chanjuan Wang¹, Xinjian Huang¹, Yue Li¹, Boyu Chen¹, Dongni Shi¹, Yunyun Xiao¹, Xiangfu Chen¹, Ying Ouyang¹, Libing Song⁴, Chuyong Lin⁵

Affiliations

¹ Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
² Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
³ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁴ Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, Guangzhou 510080, China.
⁵ Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Guangdong Esophageal Cancer Institute, Guangzhou 510060, China. Electronic address: linchuyong999@gmail.com.

PMID: 37751742
DOI: 10.1016/j.molcel.2023.08.032

Abstract

Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.

Keywords: CTNS; GSH; MFSD12; breast cancer; chemotherapy; cyst(e)ine; lysosome; mTORC1; oxidative stress; redox homeostasis.