title: Enhancing doxorubicin efficacy through inhibition of aspartate transaminase in triple-negative breast cancer cells.
abstract: 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.
authors.affiliation: Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, Liaoning 110122, People's Republic of China. Electronic address: yy25600960@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000628:therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D001219:Aspartate Aminotransferases
keywords: Aspartate transaminase; Chemotherapy; Glutamine metabolism; Triple-negative breast cancer