Autophagy, Mitochondrial Quality Control, and Oncogenesis

Jin, Shengkan

doi:10.4161/auto.2.2.2460

Cited by 154 publications

(85 citation statements)

References 38 publications

(48 reference statements)

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“…By removing aberrant organelles and limiting the production of reactive oxygen species, autophagy is believed to protect cells from genotoxic stress that may lead to cancer pathogenesis (5). This is supported by the observation that Beclin 1 and UVRAG, which are involved in autophagosome assembly, also have tumor suppressor activity (6,7).…”

supporting

confidence: 50%

Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin

Donohue¹,

Tovey²,

Vogl

et al. 2011

Journal of Biological Chemistry

116

113

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Autophagy enables cells to degrade and recycle cytoplasmic materials both as a housekeeping mechanism and in response to extracellular stress such as nutrient deprivation. Recent studies indicate that autophagy also functions as a protective mechanism in response to several cancer therapy agents, making it a prospective therapeutic target. Few pharmacological inhibitors suitable for testing the therapeutic potential of autophagy inhibition in vivo are known. An automated microscopy assay was used to screen >3,500 drugs and pharmacological agents and identified one drug, verteporfin, as an inhibitor of autophagosome accumulation. Verteporfin is a benzoporphyrin derivative used in photodynamic therapy, but it inhibits autophagy without light activation. Verteporfin did not inhibit LC3/Atg8 processing or membrane recruitment in response to autophagic stimuli, but it inhibited drug-and starvationinduced autophagic degradation and the sequestration of cytoplasmic materials into autophagosomes. Transient exposure to verteporfin in starvation conditions reduced cell viability whereas cells in nutrient-rich medium were unaffected by drug treatment. Analysis of structural analogs indicated that the activity of verteporfin requires the presence of a substituted cyclohexadiene at ring A of the porphyrin core but that it can tolerate a number of large substituents at rings C and D. The existence of an autophagy inhibitor among FDA-approved drugs should facilitate the investigation of the therapeutic potential of autophagy inhibition in vivo.

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supporting

confidence: 50%

Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin

Donohue¹,

Tovey²,

Vogl

et al. 2011

Journal of Biological Chemistry

116

113

View full text Add to dashboard Cite

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“…Impaired survival and activation of the DNA damage response are also observed in atg5 −/− iBMK cells upon exposure to metabolic stress (Mathew et al 2007), indicating that these activities result from defective autophagy rather than low Beclin1 levels. Defective autophagy compromises the ability of cells to adapt to metabolic stress, which may lead to insufficient ATP generation and accumulation of damaged mitochondria with excessive reactive oxygen species (ROS) (Jin 2006). Limiting ATP levels and/or direct DNA insult by ROS may cause replication stress and DNA damage response activation, which normally arrests cell cycle progression or triggers apoptosis, and can therefore act as a barrier to early carcinogenesis (Bartkova et al 2005;Gorgoulis et al 2005).…”

Section: Deficient Autophagy Dna Damage and Genomic Instabilitymentioning

confidence: 99%

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

Karantza‐Wadsworth

Patel²,

Kravchuk³

et al. 2007

Genes Dev.

Self Cite

753

718

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Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.

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“…[1][2][3][4] Failure of mitophagy regulation results in abnormal cellular function caused by the accumulation of damaged mitochondria, leading to many pathophysiological states. [5][6][7][8] Accumulating data suggests that mitophagy has an essential role in the regulation of the innate immune response. [9][10][11][12] When mitophagy is impaired, the increase of damaged mitochondria caused by immune stimulators results in the generation of mitochondrial ROS (reactive oxygen species) and release of mitochondrial DNA, which induces hyperactivation of the NLRP3 inflammasome, and in turn leads to over-inflammation, tissue injury and increased mortality in the host.…”

Section: Introductionmentioning

confidence: 99%

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

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Autophagy, Mitochondrial Quality Control, and Oncogenesis

Cited by 154 publications

References 38 publications

Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin

Inhibition of Autophagosome Formation by the Benzoporphyrin Derivative Verteporfin

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

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