Exploring cysteine regulation in cancer cell survival with a highly specific "Lock and Key" fluorescent probe for cysteine

• Published in: Chemical science (Cambridge) Vol. 1; no. 43; pp. 165 - 171
• Main Authors: Liu, Jing, Liu, Mengxing, Zhang, Hongxing, Wei, Xuehong, Wang, Juanjuan, Xian, Ming, Guo, Wei
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 21.11.2019
• Subjects: Cancer; Chemotherapy; Cysteine; Cystine; Depletion; Fluorescent indicators; Glutathione; NMR; Nuclear magnetic resonance; Sensitizing; Survival
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c9sc02618e

To probe the regulatory roles of cysteine (Cys) in cancer cell survival, a highly selective and sensitive fluorescent Cys probe SiR was developed by employing a novel "lock and key" strategy, which allows Cys to be detected without any interference or probe consumption caused by the intracellular high concentration of glutathione (GSH). Using SiR , we confirmed that inhibiting cystine (Cys 2 ) transporter system x c − to deplete intracellular Cys is more efficient than inhibiting glutamate-cysteine ligase GCL to deplete intracellular GSH for sensitizing cancer cells to chemotherapy. Moreover, with the probe, a possible self-protection mechanism of cancer cells was indicated: when extracellular Cys sources are blocked, cancer cells could still survive by multidrug resistance protein transporter (Mrp1)-mediated export of intracellular GSH/GSSG as sources to supply intracellular Cys for resisting detrimental oxidative stress. Based on this finding, we further confirmed that abrogating the self-protection mechanism is an even more efficient strategy for sensitizing cancer cells to chemotherapy. Using a highly specific "lock and key" fluorescent Cys probe, we confirmed that targeting Cys metabolism to deplete intracellular Cys is a more potent strategy to sensitize cancer cells to chemotherapies.