miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma

Meiying Luo, Longfei Wu, Kexin Zhang, Hong Wang, Tian Zhang, Lucas Gutierrez, Douglas O’Connell,

Peng Zhang, Yu Li, Tongtong Gao, Wenyan Ren, Yongfei Yang

Cell Death Differ. 2018 Jan 18

Speaker: Ming-Yu Shieh (謝明育)             Time: 14:00-15:00, Apr. 11, 2018

Commentator: Dr. Chi-Wu Chiang (蔣輯武老師)   Place: Room 601

Abstract:

                Glutamine metabolism is usually upregulated in many malignancies including melanoma, the most aggressive and treatment-resistant form of skin cancers. In addition to energy generation, glutamine metabolism drives production of oxidizable lipids and reactive oxygen species (ROS). To erase the cytotoxic effects of lipid oxidation and ROS, glutamine metabolism also drives production of antioxidative glutathione. Blocking glutathione production by some compounds, e.g., erastin and RSL3, increases intracellular peroxidized lipids and ROS in a Fe²⁺-dependent manner. Erastin/RSL3-induced peroxidized lipid accumulation and mitochondria damages result in ferroptosis, a special form of cell death featured by accumulation of MDA (a peroxidized lipid product) and its dependence on ROS and Fe²⁺. MicroRNAs participate in many metabolic regulation [1] and cancer development [2], but it is unknown whether miRNAs regulate ferroptosis. In this study, the authors used Ras/Raf-overactive melanoma cells with high basal levels of intracellular ROS to screen for microRNAs affecting erastin/RSL3-induced ferroptosis, and they found that miR-137 inhibits ferroptosis. Interestingly, miR-137 profoundly reduces MDA and ROS but slightly decreases Fe²⁺, suggesting that it may reduce oxidizable lipids produced from glutamine metabolism. Consistently, blocking glutamine metabolism can substitute for miR-137 to inhibit ferroptosis. Furthermore, sequence alignment shows that a glutamine importer SLC1A5 is a target of miR-137; overexpression of miR-137 decreases SLC1A5 expression and glutamine uptake. Notably, supplement with a-KG, a downstream product of glutamine metabolism, can restore ferroptosis even in the presence of miR-137, but supplement with extracellular glutamine cannot, indicating that miR-137 inhibits ferroptosis majorly through blocking an upstream step (i.e., glutamine uptake) of glutamine metabolism. In conclusion, the authors found that miR-137 reduces SLC1A5 expression, glutamine metabolism and lipid peroxidation, thus inhibiting erastin/RSL3-induced ferroptosis. Malignant cells frequently show glutamine metabolism hyperactivation, ROS overproduction and miR-137 downregulation [3-4], so they should be more susceptible to ferroptosis induced by glutathione inhibition. In addition, the levels of ROS and miR-137 may serve as useful markers to identify the cancer patients potentially suitable for ferroptosis-inducing anticancer therapies.

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