Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Ségala, Grégory; David, Marion; Médina, Philippe de; Poirot, Mathias C.; Serhan, Nizar; Vergez, François; Mougel, Aurélie; Saland, Estelle; Carayon, Kévin; Leignadier, Julie; Caron, Nicolas; Voisin, Maud; Cherier, Julia; Ligat, Lætitia; Lopez, Fréderic; Noguer, Emmanuel; Rives, Arnaud; Payré, Bruno; Saati, Talal Al; Lamazière, Antonin; Despres, Gaëtan; Lobaccaro, Jean-Marc A.; Baron, Silvère; Demur, Cécile; Toni, Fabienne de; Larrue, Clément; Boutzen, Héléna; Thomas, Fabienne; Sarry, Jean-Emmanuel; Tosolini, Marie; Picard, Didier; Record, Michel; Récher, Christian; Silvente-Poirot, Sandrine

doi:10.1038/s41467-017-01948-9

Cited by 90 publications

(117 citation statements)

References 66 publications

(85 reference statements)

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“…Although the most convincing observations of ACD have been made using lower model organisms like Caenorhabditis elegans, Drosophila melanogaster, and Dyctiostelium discoideum [5,[11][12][13], numerous studies have also demonstrated bona fide ACD in mammalian cells [14][15][16][17][18][19]. Liu et al observed that a cell-permeable Tat-Beclin 1 peptide induces a (bulk) autophagy-dependent type of cell death that could be inhibited with antagonists of Na(+), K(+)-ATPase and the authors termed this type of cell death as "autosis" [20].…”

Section: Autophagy In Cell Survival and Cell Deathmentioning

confidence: 99%

“…Other groups showed that downregulation of the AKT1/mTOR-axis using the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) induced ACD in hepatocellular carcinoma (HCC) cell lines [55]. Finally, the cholesterol metabolite dendrogenin A (DDA) induced lethal autophagy, reminiscent of ACD, in myeloma and acute myeloid leukemia in vitro and in vivo [19].…”

Section: Pro-death Autophagymentioning

confidence: 99%

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Autophagy in Cancer Cell Death

Linder

Kögel

2019

Biology

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Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.

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Section: Autophagy In Cell Survival and Cell Deathmentioning

confidence: 99%

Section: Pro-death Autophagymentioning

confidence: 99%

Autophagy in Cancer Cell Death

Linder

Kögel

2019

Biology

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“…It includes three isoforms of LC3A, LC3B, LC3C, of which LC3B is associated with autophagy levels (Wu et al 2014a). LC3 has been reported in several tumors (including ovarian cancer (Shen et al 2008), brain cancer (Ghavami et al 2014), colorectal cancer (Wu et al 2015), prostate cancer (Zhang et al 2017), breast cancer (Jiang et al 2017), melanoma (Segala et al 2017). A meta-analysis of LC3 and ovarian cancer has shown that LC3 expression is associated with FIGO stage (Zhao et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Role of the autophagy-related marker LC3 expression in hepatocellular carcinoma: a meta-analysis

Meng

Lou

Yang

et al. 2020

J Cancer Res Clin Oncol

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Background Microtubule-associated protein 1 light chain 3 (LC3), an autophagic gene, has been reported as a vital marker for many diseases and cancers. However, the role of LC3 in hepatocellular carcinoma (HCC) was not still investigated. Therefore, we conducted a meta-analysis to examine the association of LC3 with its clinicopathological and prognostic in HCC. Methods We consulted the PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure and Wan Fang databases for published studies on LC3 in HCC. Newcastle-Ottawa scale was used to screen the quality of the literature. The statistical analysis was calculated by STATA 14.2. Results Of the 1329 titles identified, 10 articles involving 949 patients in HCC were included in this meta-analysis. The results of our study show that increased LC3 expression is related to size of tumor, but not to gender, age, number of tumor, liver cirrhosis, HBsAg, TNM stage, alpha fetoprotein, vascular invasion and histological grade. Positive LC3 expression was associated with overall survival by pooled hazard ratio. Conclusions This meta-analysis indicated that positive LC3 expression was related to size of tumor, and could predict prognosis in human hepatocellular carcinoma.

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“…In the case of melanoma cells treated with THPN, a chemical compound targeting NR4A1, cell death occurs after induction of excessive mitophagy, due to NR4A1 translocation to the inner membrane of the mitochondria, causing dissipation of mitochondrial membrane potential by the permeability pore complex ANT1/VDAC [14]. Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo [15,16], displaying anticancer and chemopreventive properties in mice [17]. Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death [18], which seems to be mediated by releasing BECN1 in a model of cigarette smokeinduced autophagic cell death [19].…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

et al. 2020

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NR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and posttranslational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.

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Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Cited by 90 publications

References 66 publications

Autophagy in Cancer Cell Death

Autophagy in Cancer Cell Death

Role of the autophagy-related marker LC3 expression in hepatocellular carcinoma: a meta-analysis

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

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