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 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.

Automated summary

Cyst(e)ine plays a crucial role in the synthesis of glutathione and its storage in lysosomes helps cancer cells maintain redox homeostasis. Breast cancer cells upregulate MFSD12 to increase lysosomal cyst(e)ine storage, which is released to maintain GSH levels and buffer oxidative stress. mTORC1 regulates MFSD12 by phosphorylating residue T254, and this switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, enhancing cell fitness. MFSD12 mutation inhibits its function and suppresses tumor progression, while its overexpression correlates with poor chemotherapy response and prognosis in breast cancer patients.