Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102

Abstract

Purpose: To investigate the metabolism of SS and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. Experimental Design: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from a SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements intracellular ROS. The susceptibility of ME1 null SS to ferroptosis induction was interrogated in in vitro and in vivo. Results: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and a SS tumor model. Investigation of SS glucose metabolism revealed that ME1 null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1 null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1 null SS demonstrate significantly increased tumor response to ACX`T-3102 compared to ME1 expressing controls. Conclusions: These findings demonstrate the translational potential of targeting redox homeostasis in ME1 null cancers, and establish the preclinical rational for a phase 1 trial of ACXT-3102 in synovial sarcoma patients.

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

“…45,46,52 ME1 has also been identified as a ferroptosis defense protein in hepatic ischemia/reperfusion injury and synovial sarcoma. 60,61 Our work establishes a novel connection between PK and ME1 as well as their roles in ferroptosis in pancreatic cancer. Additionally, our study shows that inhibition of ME1 provides a route to promote ferroptosis and circumvent PDAC metabolic defense strategies for surviving low cystine conditions.…”

Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis

“…S7 F ), suggesting that MYC and ME2 affect glutamine oxidation but not reductive carboxylation in Jurkat cells. Furthermore, we performed 1,2- 13 C glucose–tracing experiment ( 26 , 31 ). Consistent with the results for glucose consumption, neither MYC knockdown nor ME2 overexpression affected glucose metabolism through glycolysis or pentose phosphate pathway in Jurkat cells ( Fig.…”

“…We previously found that p53 inhibits ME2 including ME1 transcription, and reciprocally, ME1 and ME2 inhibit p53 activation through different mechanisms ( 21 ). A recent study reported an important role for ME1 in the regulation of redox homeostasis in synovial sarcoma ( 26 ). Here, we report that ME2 is a target of MYC and plays a critical role in MYC-driven T cell lymphomagenesis.…”

Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

“…[31,32] A recent study by Brashears et al showed that synovial sarcoma lacks ME1 expression which drives decrease in intracellular NADPH and GSH levels. [33,34] Interestingly, ME1 deficiency render synovial sarcoma cells sensitive to erastin-induced ferroptosis, but resistant to GSH depletion-induced cell death. Reprogramming of redox homeostasis in the context of ME1 absence may explain how these cells adapt to be less dependent on GSH.…”