阿霉素
三阴性乳腺癌
心理压抑
活性氧
癌症研究
细胞内
癌细胞
谷氨酰胺
化学
化疗
生物
癌症
药理学
乳腺癌
生物化学
内科学
医学
基因表达
氨基酸
基因
标识
DOI:10.1016/j.bbrc.2016.04.061
摘要
Triple-negative breast cancer (TNBC) cell lines are identified to overexpress aspartate transaminase (GOT1), which can potentially control the intracellular levels of reactive oxygen species (ROS) through NADPH synthesis and enhances tumor growth. In this study, the impact of GOT1 on the efficacy of doxorubicin was investigated. Following doxorubicin administration, TNBC cells acquire metabolic alteration, causing increased glutamine flux for the synthesis of aspartate which can be converted into OAA by GOT1. Subsequently, this OAA is converted into malate and then pyruvate, maintaining the NADP(+)/NADPH ratio which neutralize doxorubicin-induced oxidative stress. Repression of GOT1 using the shRNAs for GOT1 resulted in doxorubicin-induced formation of ROS, thereby increasing doxorubicin sensitivity. The enhanced efficacy of doxorubicin by simultaneous repression of GOT1 was also indicated in an in vivo tumor model of TNBC. These results demonstrate that targeting GOT1 in TNBCs may provide a novel therapeutic approach for improving the efficacy of chemotherapy in patients with these refractory tumors.
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