HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications

Zhao, Youbo; Li, Menghuan; Yao, Xuemei; Yang, Fei; Lin, Zhenghong; Li, Zhengguo; Cai, Kaiyong; Zhao, Yanli; Luo, Zhong

doi:10.1016/j.celrep.2020.108487

Cited by 246 publications

(175 citation statements)

References 56 publications

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“…In contrast, AMPK-mediated phosphorylation of Beclin 1 promotes ferroptotic cell death in colon cancer cells (e.g., PANC1; Song et al, 2018a) and noncancer cells (e.g., HTR8/Svneo; Han et al, 2020)). Moreover, AMPK-mediated stearoyl-CoA desaturase (SCD/SCD1) downregulation promotes ferroptosis in hepatocellular carcinoma cells by inhibiting production of monounsaturated fatty acids (MUFAs) (Zhao et al, 2020). Interestingly, knockdown of PDK4 increased AMPK kinase activity following treatment with erastin or RSL3 in PANC1 cells (Figure 4L).…”

Section: Figure 2 Pyruvate Oxidation-dependent Fatty Acid Synthesis Facilitates Ferroptosismentioning

confidence: 99%

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

et al. 2021

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Section: Figure 2 Pyruvate Oxidation-dependent Fatty Acid Synthesis Facilitates Ferroptosismentioning

confidence: 99%

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

et al. 2021

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“…Hence, targeting the lactate‐dependent AMPK‐SCD‐MUFA axis may restore ferroptosis sensitivity in HCC cells. [ 62 ] It is worth noting that AMPK plays a dual role in ferroptosis. Depending on its phosphorylated substrates (e.g., acetyl‐CoA carboxylase [ACAC/ACC1] [ 63 ] and beclin 1 [BECN1]), [ 64 ] the ferroptotic response can be negatively or positively regulated by AMPK.…”

Section: Lipid Synthesis In Ferroptosismentioning

confidence: 99%

Lipid Metabolism in Ferroptosis

et al. 2021

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Lipid metabolism is a complex biochemical process that participates in the regulation of cell survival and death. Ferroptosis is a form of iron‐dependent regulated cell death driven by abnormal lipid metabolism, leading to lipid peroxidation and subsequent plasma membrane rupture. A variety of antioxidant systems and membrane repair pathways can diminish oxidative damage, enabling survival and growth in response to ferroptotic signals. Such impairment of ferroptosis machinery is implicated in various pathological conditions and diseases, especially cancer and tissue damage. It is discussed here how lipid metabolism pathways, including lipid synthesis, degradation, storage, transformation, and utilization, modulate ferroptosis sensitivity or tolerance in different models, especially cancer.

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“…More specifically, AMPK activation phosphorylates and thus inhibits acetyl-CoA carboxylase 1 and 2 (ACC1/2), leading to a reduced conversion of acetyl-CoA to malonyl-CoA required for the biosynthesis PUFAs [183], which in turn protects cells from lipid peroxidation and ferroptosis [183,184]. Moreover, AMPK activation leads to downregulation of SREBP (sterol regulatory element-binding protein 1) and its downstream SCD1 (stearoyl-coenzyme A (CoA) desaturase-1), the primary enzyme for the biosynthesis of anti-ferroptotic MUFAs [185]. Altogether, these studies thus highlight a critical role of mitochondrial metabolism in regulation of lipid peroxidation and ferroptosis via the metabolic process including glutaminolysis-TCA cycle-ETC-ATP production (Figure 3).…”

Section: Mitochondrial Glutaminolysis-tca-etc Axis Modulating Ferroptosismentioning

confidence: 99%

The Multifaceted Regulation of Mitochondria in Ferroptosis

Wang

et al. 2021

Life

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Ferroptosis is characterized as a novel form of regulated cell death, which is initiated by the lethal accumulation of lipid peroxidation catalyzed by cellular labile free iron. This iron driven cell death sharply differs from other well characterized forms of regulated cell death at morphological, genetic and biochemical levels. Increasing research has elaborated a high relevance between dysregulated ferroptosis and the pathogenesis of degenerative diseases and organs injury in human patients. Additionally, targeted induction of ferroptosis is considered as a potentially therapeutic design for the clinical intervention of other therapy-resistant cancers. It is well understood that mitochondria, the cellular powerhouse, determine several types of regulated cell death. Recently, compromised mitochondrial morphology and functionalities have been primarily formulated in ferroptosis. Several mitochondria associated proteins and metabolic processes have been elaborated to fine-tune ferroptotic program. Herein, we critically review the recent advances in this booming field, with focus on summarizing the multifaceted mitochondrial regulation of ferroptosis and providing a perspective on the potential biochemical basis. Finally, we are attempting to shed light on an integrative view on the possibility of mitochondria- and ferroptosis-targeting therapeutics as novel treatment designs for the intervention of ferroptosis related diseases.

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HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications

Abstract: Highlights d Lactate uptake promotes ATP production to upregulate SREBP1 and SCD1 d Lactate mediates the production of ferroptosis-related lipids in cancer cells d HCAR1/MCT1 inhibition sensitizes cancer cells to ferroptosis induction

Cited by 246 publications

References 56 publications

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

Lipid Metabolism in Ferroptosis

The Multifaceted Regulation of Mitochondria in Ferroptosis

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