miR‐9 regulates ferroptosis by targeting glutamic‐oxaloacetic transaminase GOT1 in melanoma

Zhang, Kexin; Wu, Long‐Fei; Zhang, Peng; Luo, Meiying; Du, Jing; Gao, Ting; O’Connell, Douglas; Wang, Gaoyang; Wang, Hong; Yang, Yongfei

doi:10.1002/mc.22878

Cited by 142 publications

(98 citation statements)

References 56 publications

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“…Knockdown of the transaminase GOT1 could also inhibit cysteine deprivation-induced ferroptosis in MEFs ( Figure 1). 17,20 However, the role of glutaminolysis in ferroptosis regulation is more complex. Glutamate dehydrogenase 1 (GLUD1) converts glutamate into αKG through the glutamate deamination.…”

Section: Glutaminolysis Is Indispensable For Cysteine Deprivation-imentioning

confidence: 99%

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ding

et al. 2019

J Cellular Molecular Medi

480

347

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Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron‐dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

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Section: Glutaminolysis Is Indispensable For Cysteine Deprivation-imentioning

confidence: 99%

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ding

et al. 2019

J Cellular Molecular Medi

480

347

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“…Ample evidence proves miRNAs as key regulators during hepatocarcinogenesis (Giordano & Columbano, 2013). Interestingly, recent studies have demonstrated that miRNAs, such as miR‐9 (Zhang et al, 2018) and miR‐137 (Luo et al, 2018), participate in ferroptosis. Here, miR‐214‐3p (miR‐214), an upstream regulator of ATF4 (Li et al, 2015; Wang et al, 2013), drew our attention.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

107

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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“…Additionally, anti-miR-9 treatment allows the production of high levels of α-kG through GOT activity. These findings indicate that miR-9 regulates glutaminolysis through GOT1 ablation, and is considered a negative regulator in melanoma cells [111] (Figure 2).…”

Section: Mir-9mentioning

confidence: 85%

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

Ortiz-Pedraza

Muñoz-Bello

Olmedo-Nieva

et al. 2020

IJMS

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Cancer cells exhibit exacerbated metabolic activity to maintain their accelerated proliferation and microenvironmental adaptation in order to survive under nutrient-deficient conditions. Tumors display an increase in glycolysis, glutaminolysis and fatty acid biosynthesis, which provide their energy source. Glutamine is critical for fundamental cellular processes, where intermediate metabolites produced through glutaminolysis are necessary for the maintenance of mitochondrial metabolism. These include antioxidants to remove reactive oxygen species, and the generation of the nonessential amino acids, purines, pyrimidines and fatty acids required for cellular replication and the activation of cell signaling. Some cancer cells are highly dependent on glutamine consumption since its catabolism provides an anaplerotic pathway to feed the Krebs cycle. Intermediate members of the glutaminolysis pathway have been found to be deregulated in several types of cancers and have been proposed as therapeutic targets and prognostic biomarkers. This review summarizes the main players in the glutaminolysis pathway, how they have been found to be deregulated in cancer and their implications for cancer maintenance. Furthermore, non-coding RNAs are now recognized as new participants in the regulation of glutaminolysis; therefore, their involvement in glutamine metabolism in cancer is discussed in detail.Int. J. Mol. Sci. 2020, 21, 2872 2 of 26 an increased glucose consumption in relation to normal differentiated tissues. Now we know that glutamine metabolism is as important as glucose metabolism for the production of macromolecules in cancer [1].Glutamine is an abundant amino acid involved in energy production, homeostasis in pro/antioxidant species and the activation of signaling pathways in cancer. In addition to the antioxidant glutathione (GSH), nucleotides, lipids and amino acids are formed from glutamine metabolism. All of these are needed for many metabolic functions such as growth, proliferation, cell survival and defense against oxidative stress [2]. Glutamine contributes, with reduced nitrogen, to the de novo biosynthesis of diverse nitrogen-containing compounds, such as purine and pyrimidine nucleotides, glucosamine-6-phosphate and nonessential amino acids.As glutamine is the most abundant amino acid in the blood and muscle tissue, normal proliferating cells use glutamine metabolism as an energy source, mediated by its catabolic products, glutamate and α-ketoglutarate (α-kG), the latter being an intermediate of the tricarboxylic acid cycle (TCA) or Krebs cycle [3]. In 1950, Harry Eagle observed that HeLa tumor cells require an excess of glutamine, in relation to other amino acids in the culture medium, for optimal growth. Furthermore, it has been reported that tumors consume glutamine faster than the surrounding normal tissue [4]. Moreover, most cancer cells are dependent on glutamine being unable to survive under glutamine starvation, an effect that has been termed glutamine addiction [5]. Various types of cancers are high...

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miR‐9 regulates ferroptosis by targeting glutamic‐oxaloacetic transaminase GOT1 in melanoma

Cited by 142 publications

References 56 publications

Molecular mechanisms of ferroptosis and its role in cancer therapy

Molecular mechanisms of ferroptosis and its role in cancer therapy

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

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