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

Luo, Meiying; Wu, Long‐Fei; Zhang, Kexin; Wang, Hong; Zhang, Tian; Gutiérrez, Lucas; O’Connell, Douglas; Zhang, Peng; Yu, Li; Gao, Ting; Ren, Wenyan; Yang, Yongfei

doi:10.1038/s41418-017-0053-8

Cited by 328 publications

(257 citation statements)

References 52 publications

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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

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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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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

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“…The role of microRNAs in the regulation of ferroptosis has also been demonstrated in melanoma ( Figure 4). miR-137 negatively regulated ferroptosis, which was shown both in vitro and in vivo, as it directly inhibited glutamine transporter SLC1A5 in melanoma cells [208]. It has been demonstrated that ectopic expression of miR-137 suppressed SLC1A5 that was associated with reduced uptake of glutamine and accumulation of malondialdehyde [208].…”

Section: Ferroptosis In Melanomamentioning

confidence: 99%

“…miR-137 negatively regulated ferroptosis, which was shown both in vitro and in vivo, as it directly inhibited glutamine transporter SLC1A5 in melanoma cells [208]. It has been demonstrated that ectopic expression of miR-137 suppressed SLC1A5 that was associated with reduced uptake of glutamine and accumulation of malondialdehyde [208]. Furthermore, it has been shown that miR-9 inhibited ferroptosis by targeting glutamicoxaloacetic transaminase 1 (GOT1), which mediates the conversion of glutamate to α-ketoglutarate [209].…”

Section: Ferroptosis In Melanomamentioning

confidence: 99%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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“…When miR-137 was ectopically expressed in melanoma cells, it was found to bind to SLC1A5 mRNA, inhibiting SLC1A5 glutamine transporter translation. This event induced a decrease in glutamine uptake, which also prevented ferroptosis-related cell death, since glutaminolysis sensitizes to ferroptosis under certain conditions [108] (Figure 2). Another study also demonstrated that the glutamine transporter ASCT2 is a target of miR-137 that regulates its expression, without affecting GLS [109].…”

Section: Mir-450amentioning

confidence: 99%

“…When miR-137 was inhibited in colon epithelial cell lines, the levels of ASCT2 transporter increased. Dong et al (2017) [109] reported that [108] demonstrated that miR-137 acts as a tumor suppressor, regulating two crucial elements of glutamine metabolism, GLS and SLC1A5 (ASCT2). When analyzing melanoma tissues, miR-137 expression was found to be decreased, while GLS was overexpressed in relation to the adjacent normal tissues.…”

Section: Mir-450amentioning

confidence: 99%

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-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma

Cited by 328 publications

References 52 publications

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

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

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

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