Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

Wang, Weijia; Wang, Yuan; Hou, Peipei; Li, Feng-wei; Zhou, Bo; Chen, Hang-zi; Bian, Xueli; Cai, Qixu; Xing, Yong-zhen; He, Jie; Zhang, Hongkui; Huang, Pei‐Qiang; Lin, Tianwei; Wu, Qiao

doi:10.1016/j.chembiol.2015.06.023

Cited by 23 publications

(18 citation statements)

References 49 publications

(50 reference statements)

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“…Accelerated autophagy is believed to be an anticancer mechanism for a variety of agents. Nur77 agonists induce autophagic cell death in melanoma cells [ 5 ]. Rapamycin, an mTOR inhibitor, induces autophagic cell death in MG63 osteosarcoma cells [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

Kang

Kim

et al. 2018

J Exp Clin Cancer Res

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BackgroundLigand-dependent activation of the G-protein coupled receptor 119 (GPR119) lowers blood glucose via glucose-dependent insulin secretion and intestinal glucagon-like peptide-1 production. However, the function of GPR119 in cancer cells has not been studied.MethodsGPR119 expression was assessed by real-time qPCR and immunohistochemistry in human breast cancer cell lines and breast cancer tissues. Cell proliferation and cell cycle analyses were performed by Incucyte® live cell analysis system and flow cutometry, respectively. Autophagy activity was estimeated by western blottings and LC3-GFP transfection.ResultsmRNA or protein expression of GPR119 was detected in 9 cancer cell lines and 19 tissue samples. Cotreatment with GPR119 agonist (MBX-2982 or GSK1292263) significantly potentiated gefitinib-induced cell growth inhibition in gefitinib-insensitive MCF-7 and MDA-MB-231 breast cancer cells. We observed that caspase-3/7 activity was enhanced with the downregulation of Bcl-2 in MCF-7 cells exposed to MBX-2982. Gefitinib-induced autophagy is related with cancer cell survival and chemoresistance. GPR119 agonists inhibit gefitinib-induced autophagosome formation in MCF-7 and MDA-MB-231 cells. MBX-2982 also caused a metabolic shift to enhanced glycolysis accompanied by reduced mitochondrial oxidative phosphorylation. MBX-2982 increased intracellular (~ 2.5 mM) and extracellular lactate (~ 20 mM) content. Gefitinib-mediated autophagy was suppressed by 20 mM lactate in MCF-7 cells.ConclusionsGPR119 agonists reduced mitochondrial OXPHOS and stimulated glycolysis in breast cancer cells, with consequent overproduction of lactate that inhibited autophagosome formation. Because autophagy is crucial for the survival of cancer cells exposed to TKIs, GPR119 agonists potentiated the anticancer effects of TKIs.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0949-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

Kang

Kim

et al. 2018

J Exp Clin Cancer Res

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“…Apoptotic stimuli induce an interaction between Bcl-2 and Nur77 at the mitochondrial surface, where Nur77 converts Bcl-2 from performing an anti-apoptotic role to a pro-apoptotic role (Chen et al, 2008;Lin et al, 2004). 4,nonan-1-one), a Nur77-targeting compound, induces inner mitochondrial translocation of Nur77, consequently promoting mitochondrial autophagy by facilitating an interaction between Nur77 and ANT1 (Wang et al, 2014(Wang et al, , 2015). Here we further show that glucose deprivation-induced Nur77-TPb association in mitochondria is important for melanoma cells to adapt to metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

Wang

Zheng

et al. 2018

Molecular Cell

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Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

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“…Inhibiting the interaction between p38α and Nur77, and inhibiting the p38α-mediated phosphorylation of Nur77 attenuates the lipopolysaccharide-induced hyperinflammatory response ( 67 ). The LBD of Nur77 binds to Akt2, and the phosphorylation of Akt2 can interfere with the migration of Nur77 to the cytoplasm and localization of Nur77 to the mitochondria, which can result in autophagy ( 40 , 68 ).…”

Section: Genomic and Non-genomic Functions Of The Orphan Receptor Nurmentioning

confidence: 99%

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Chen

2018

Mol Med Report

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Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77/TR3/NGFIB), a member of the nuclear receptor superfamily, is expressed as an early response gene to regulate the expression of multiple target genes. Nur77 has the typical structure of a nuclear receptor, including an N-terminal domain, a DNA binding domain, and a ligand-binding domain. The expression and localization of Nur77 are closely associated with its roles in cell proliferation and apoptosis. Nur77 was first identified as an orphan receptor, the endogenous ligand of which has not yet been identified; however, an increasing number of compounds targeting Nur77 have been reported to have beneficial effects in the treatment of cancer and other diseases. This review provides a brief overview of the identification, structure, expression and localization, transcriptional role and non-genomic function of Nur77, and summarizes the ligands that have been shown to interact with Nur77, including cytosporone B, cisplatin, TMPA, PDNPA, CCE9, THPN, Z-ligustilide, celastrol and bisindole methane compounds, which may potentially be used to treat cancer in humans.

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Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

Cited by 23 publications

References 49 publications

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy

Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

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