Inhibition of glutathione metabolism attenuates esophageal cancer progression

Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with regard to mortality and prognosis, and the 5-year survival rate for all patients diagnosed with ESCC remains poor. A better understanding of the biological mechanisms of ESCC tumorigenesis and progression is of great importance to improve treatment of this disease. In this study, we demonstrated that the glutathione metabolism pathway is highly enriched in ESCC cells compared with normal esophageal epithelial cells in an in vivo mouse model. In addition, treatment with L-buthionine-sulfoximine (BSO) to deplete glutathione decreased the ESCC tumor burden in mice, thus demonstrating the critical role of glutathione metabolism in ESCC progression. BSO treatment also led to decreased cell proliferation and activation of cell apoptosis in ESCC. Finally, BSO treatment blocked NF-kB pathway activation in ESCC. Our study reveals a new pathway that regulates ESCC progression and suggests that inhibition of glutathione metabolism may be a potential strategy for ESCC treatment. Inhibiting the production of the antioxidant molecule glutathione shows potential for treating a common form of deadly esophageal cancer. Liang Peng and colleagues at the Chinese PLA General Hospital in Beijing with co-workers elsewhere in China and the USA detected increased production of glutathione in a mouse model of esophageal squamous cell carcinoma. Treating the mice with a drug that inhibits glutathione production reduced the number of tumors and allowed the mice to maintain a healthier body weight. The work revealed details of a molecular pathway regulating progression of the cancer. The researchers have not yet demonstrated that the treatment could increase survival rates, as all the mice were sacrificed for analysis. They suggest, however, that their procedure could be used to test the anticancer potential of drugs that inhibit glutathione production.