AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells

Meyer, Nina; Zielke, Svenja; Michaelis, Jonas B.; Linder, Benedikt; Warnsmann, Verena; Rakel, Stefanie; Osiewacz, Heinz; Fulda, Simone; Mittelbronn, Michel; Münch, Christian; Behrends, Christian; Kögel, Donat

doi:10.1080/15548627.2018.1476812

Cited by 90 publications

(85 citation statements)

References 79 publications

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“…Silencing of heme oxygenase 1 (HMOX1) and the mitophagy receptors BCL2-interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L), significantly attenuated AT-101-dependent mitophagy and cell death. Collectively, these data suggest that early mitochondrial dysfunction and HMOX1 over activation synergize to trigger lethal mitophagy following AT-101 treatment of GBM cells (Figure 3) [81,82].…”

Section: Pro-death Mitophagy Triggered By Gossypol/at-101mentioning

confidence: 80%

“…In particular, we found that AT-101 impaired mitochondrial respiration and rapidly triggered mitochondrial membrane depolarization. We also observed the engulfment of mitochondria within autophagosomes using electron microscopy (EM), and a significant reduction of mitochondrial mass and proteins, as determined with the mito-Keima assay and by global proteomic analysis of U87 and U343 GBM cells, that neither depend on the presence of Parkin nor the proapoptotic BCL-2 family proteins BAX and BAK1 [73,81,82].…”

Section: Pro-death Mitophagy Triggered By Gossypol/at-101mentioning

confidence: 90%

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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: Pro-death Mitophagy Triggered By Gossypol/at-101mentioning

confidence: 80%

Section: Pro-death Mitophagy Triggered By Gossypol/at-101mentioning

confidence: 90%

Autophagy in Cancer Cell Death

Linder

Kögel

2019

Biology

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“…Heme is also the main target of HMOX‐1 (Gozzelino et al , ), an antioxidant factor which was highly up‐regulated in response to HIV‐1 replication in our experiments. Intriguingly, the PML‐depleting drug ATO is known to induce upregulation of HMOX‐1 (Meyer et al , ), further suggesting the possibility that HMOX‐1 expression might respond to lowered PML levels.…”

Section: Discussionmentioning

confidence: 99%

Alterations of redox and iron metabolism accompany the development of HIV latency

et al. 2020

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HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4 + T cells, thus hampering efforts for a cure. HIV-1 infection is accompanied by metabolic alterations, such as oxidative stress, but the effect of cellular antioxidant responses on viral replication and latency is unknown. Here, we show that cells survive retroviral replication, both in vitro and in vivo in SIVmacinfected macaques, by upregulating antioxidant pathways and the intertwined iron import pathway. These changes are associated with remodeling of promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML NBs are hyper-SUMOylated and that PML protein is degraded via the ubiquitinproteasome pathway in productively infected cells, before latency establishment and after reactivation. Conversely, normal numbers of PML NBs were restored upon transition to latency or by decreasing oxidative stress or iron content. Our results highlight antioxidant and iron import pathways as determinants of HIV-1 latency and support their pharmacologic inhibition as tools to regulate PML stability and impair latency establishment.

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“…Cytoprotective roles of autophagy have for example been illustrated in several models of neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), where the selective removal of pathological protein aggregates or damaged organelles via selective autophagy can support cell survival 10,22-24 .Since the induction of autophagy offers novel options to modulate human diseases 25 , the identification and characterization of compounds that stimulate autophagy has attracted special interest. In recent years, several natural compounds, small molecules and Food & Drug Administration (FDA)-approved drugs have been reported to induce autophagy and ACD under different cellular conditions and in different cell types [26][27][28][29][30] . Furthermore, triggering compound-induced autophagy and ACD has attracted particular interest, since many cancer types acquire loss-of-function mutations in conventional cell death pathways, like apoptosis, rendering them resistant against conventional chemotherapies 31 .Recently, we demonstrated that STF-62247 and pimozide trigger autophagy in glioblastoma (GBM) cells leading to ACD 30 .…”

mentioning

confidence: 99%

“…Since the induction of autophagy offers novel options to modulate human diseases 25 , the identification and characterization of compounds that stimulate autophagy has attracted special interest. In recent years, several natural compounds, small molecules and Food & Drug Administration (FDA)-approved drugs have been reported to induce autophagy and ACD under different cellular conditions and in different cell types [26][27][28][29][30] . Furthermore, triggering compound-induced autophagy and ACD has attracted particular interest, since many cancer types acquire loss-of-function mutations in conventional cell death pathways, like apoptosis, rendering them resistant against conventional chemotherapies 31 .…”

mentioning

confidence: 99%

STF-62247 and pimozide induce autophagy and autophagic cell death in mouse embryonic fibroblasts

Kinzler

Zielke

Kardo

et al. 2020

Sci Rep

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Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential of two novel autophagyinducing compounds, i.e. STF-62247 and pimozide, to stimulate autophagy as well as autophagic cell death (ACD) using mouse embryonic fibroblasts (MEFs) as a cellular model. Importantly, both STF-62247 and pimozide triggered several hallmarks of autophagy in MEFs, i.e. enhanced levels of LC3B-II protein, its accumulation at distinct cytosolic sites and increase of the autophagic flux. Intriguingly, autophagy induction by STF-62247 and pimozide resulted in cell death that was significantly reduced in ATG5-or ATG7-deficient MEFs. Consistent with ACD induction, pharmacological inhibitors of apoptosis, necroptosis or ferroptosis failed to protect MEFs from STF-62247-or pimozide-triggered cell death. Interestingly, at subtoxic concentrations, pimozide stimulated fragmentation of the mitochondrial network, degradation of mitochondrial proteins (i.e. mitofusin-2 and cytochrome c oxidase IV (COXIV)) as well as a decrease of the mitochondrial mass, indicative of autophagic degradation of mitochondria by pimozide. In conclusion, this study provides novel insights into the induction of selective autophagy as well as ACD by STF-62247 and pimozide in MEFs.Besides bulk autophagy, mitophagy is known as one of the best-characterized forms of selective autophagy. During mitophagy, distinct receptors selectively recognize mitochondria and bridge them to LC3 proteins, which enables lysosomal degradation of the entire organelles 9 . To date, several receptors have been reported to selectively bind to mitochondria, among these are B-cell lymphoma 2 nineteen kilodalton interacting protein 3 (BNIP3), Nix, BCL-2-like protein 13 (BCL2-L-13), FUN14 domain-containing protein 1 (FUNDC1), p62, Optineurin, Calcium-binding and coiled-coil domain-containing protein 2 (NDP52), Protein NBR1 homolog (NBR1) and TAX1-binding protein 1 (TAX1BP1) 10 . A well-characterized model of mitophagy is Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN)-induced kinase 1 (PINK1)/ Parkin-mediated mitophagy, in which Parkin becomes phosphorylated by the E3 ligase PINK1 and subsequently builds up ubiquitin chains on mitochondria, which are in turn recognized by selective autophagy receptors 11 .Autophagy is induced in response to starvation, oxidative stress and accumulation of misfolded proteins 12-14 and can serve to provide novel building blocks in response to high energy demands or as a protein quality control mechanism to remove protein aggregates or damaged organelles 15 . Depending on the cellular context, autophagy may exert dual roles in the regulation of programmed cell death, i.e. lethal and/or cytoprotective. Stimulation of autophagy can promote cell death referred to as ACD [16][17][18][19] . Although the molecular signals that trigger ACD are not yet fully understood, there are well-acknowledged criteria to class...

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AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells

Cited by 90 publications

References 79 publications

Autophagy in Cancer Cell Death

Autophagy in Cancer Cell Death

Alterations of redox and iron metabolism accompany the development of HIV latency

STF-62247 and pimozide induce autophagy and autophagic cell death in mouse embryonic fibroblasts

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