Cysteine is a limiting factor for glioma proliferation and survival

Molecular Oncology

Christel C. Herold‐Mende¹  Ana Dios‐Esponera²  Jinkyu Jung³  Victor Ruiz‐Rodado³  Lumin Zhang³  Meili Zhang³  Mark R. Gilbert³  Adrian Lita³  Tyrone Dowdy³  Mioara Larion³  Kevin Camphausen⁴  Tamalee Kramp⁴ 

[1] Division of Neurosurgical Research Department of Neurosurgery University Hospital Heidelberg Germany;Fred Hutchinson Cancer Research Center Seattle WA USA;Neuro‐Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA;Radiation Oncology Branch Center for Cancer Research National Institutes of Health Bethesda MD USA;

关键词: cysteine;    diet;    glioma;    glutathione;    metabolism;   

DOI  :  10.1002/1878-0261.13148

来源: DOAJ

【 摘 要 】

Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

【 授权许可】

Unknown