RESUMEN
Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.
Asunto(s)
Antioxidantes , Glutamato-Cisteína Ligasa , Glutamato-Cisteína Ligasa/metabolismo , Cisteína/metabolismo , Inhibidores Enzimáticos , Glutatión/metabolismoRESUMEN
To investigate the effect of taurine on the sympathetic nervous system, I observed pressor responses of perfused mesenteric arteries by electrical stimulation and baro-reflex sensitivity of spontaneously hypertensive rats (SHR/Izm) and control Wistar-Kyoto rats (WKY/Izm) treated with taurine. Taurine added to the perfusate suppressed norepinephrine (NE) overflow and the pressor response mediated by electrical stimulation of isolated perfused mesenteric arteries. Taurine showed a greater suppressive effect on NE overflow and the pressor response mediated by electrical stimulation in SHR/Izm rats than in WKY/Izm rats. Increment of renal sympathetic nerve activity induced by jet-air stress was suppressed in SHR/Izm rats treated with 3% taurine. The arterial baro-reflex sensitivity was more sensitive in SHR/Izm rats treated with taurine than in those exposed to no taurine. These data suggest that taurine lowers blood pressure directly via the suppression of NE release from the peripheral sympathetic nerve and the improvement of impaired baro-reflex sensitivity.