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

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 1...

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Published in:Molecular cell 2023-10, Vol.83 (19), p.3502-3519.e11
Main Authors: He, Lixin, Chen, Jinxin, Deng, Pinwei, Huang, Shumei, Liu, Pian, Wang, Chanjuan, Huang, Xinjian, Li, Yue, Chen, Boyu, Shi, Dongni, Xiao, Yunyun, Chen, Xiangfu, Ouyang, Ying, Song, Libing, Lin, Chuyong
Format: Article
Language:English
Subjects:
acidification
breast cancer
breast neoplasms
chemotherapy
CTNS
cyst(e)ine
drug therapy
glutathione
GSH
homeostasis
lysosome
lysosomes
MFSD12
mTORC1
mutants
neoplasm progression
oxidative stress
prognosis
redox homeostasis
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Summary: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. [Display omitted] •Lysosomal cyst(e)ine storage and release maintains GSH levels for ROS buffering•MFSD12 is phosphorylated by mTORC1 at T254 to control lysosomal cyst(e)ine storage•MFSD12-T254A mutant acts as a dominant-negative inhibitor of MFSD12 functions•MFSD12 upregulation induces chemoresistance and poor prognosis in breast cancer He et al. report that MFSD12 upregulation in breast cancer increases the lysosomal cyst(e)ine storage, providing a ready source of cyst(e)ine for GSH synthesis, which is regulated by mTORC1 to fine-tune redox homeostasis and enhance cell fitness.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2023.08.032