Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition

Bray, Kevin; Mathew, Robin; Lau, Alexandria; Kamphorst, Jurre J.; Fan, Jianqing; Chen, Jim; Chen, Hsin Yi; Ghavami, Anahita; Stein, Mark N.; DiPaola, Robert S.; Zhang, Donna; Rabinowitz, Joshua D.; White, Eileen

doi:10.1371/journal.pone.0041831

Cited by 131 publications

(101 citation statements)

References 72 publications

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“…Consistent with a protective role for autophagy, inhibition of autophagic function with chloroquine can induce cancer cell death through necroptosis. 3 Persistent autophagy can, however, eliminate cancer cells. Enhanced mammary tumorigenesis has been observed in heterozygous Becn1 +/− mice with reduced expression of an essential component required for autophagy.…”

Section: Introductionmentioning

confidence: 99%

DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

et al. 2014

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Section: Introductionmentioning

confidence: 99%

DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

et al. 2014

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“…As discussed above, caspases can actively suppress necroptosis. Autophagy has also been shown to directly inhibit necroptosis by degrading the kinase RIPK1 (Bray et al, 2012). In that study, chemical initiation of autophagy, while inhibiting its completion, led to robust RIPK1-and RIPK3-dependent necroptosis.…”

Section: Interplay Between Autophagy and Other Cell Death Pathwaysmentioning

confidence: 96%

Die another way – non-apoptotic mechanisms of cell death

Tait

Ichim

Green

2014

Journal of Cell Science

315

246

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Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as necroptosis and pyroptosis. These non-apoptotic cell death modalities can be either triggered independently of apoptosis or are engaged should apoptosis fail to execute. In this Commentary, we discuss several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death. We outline what we know about their mechanism, potential roles in vivo and define outstanding questions. Finally, we review data arguing that the means by which a cell dies actually matters, focusing our discussion on inflammatory aspects of cell death.

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“…In this setting autophagy mitigates ER stress caused by BRAF V600E inhibition, highlighting the additional importance of therapy-induced autophagy as a resistance mechanism (46). Indeed, there are other examples of therapy-induced autophagy functioning as a resistance mechanism, suggesting that augmentation of the anticancer activity of autophagy inhibitor therapeutics may be generally applicable (47)(48)(49)(50).…”

Section: Acknowledgmentsmentioning

confidence: 98%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

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1,109

965

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Autophagy is a tissue-specific regulator of homeostasis and survivalAutophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Low levels of basal autophagy prevent the gradual accumulation of damaged proteins and organelles in tissues that is toxic over time; thus, autophagy plays an important role in protein and organelle quality control (1). Identification of the autophagy substrates that are deregulated in autophagy-deficient cells and tissues is important to understand the biological role and tissue specificity of autophagy. Determination of the global impact of autophagy on the cellular proteome would be a significant advance, as we are only beginning to understand the broad scope of autophagy substrates and the functional consequence of deregulating their degradation and recycling.Some tissues such as liver, brain, and muscle are particularly dependent on autophagy to prevent the buildup of damaged mitochondria and protein aggregates containing the autophagy substrate p62/SQSTM1 (p62) and ubiquitin (1). Accumulation of defective mitochondria that results from impaired autophagy can perturb metabolism and generate oxidative stress (2). Autophagy also mitigates ER stress, and autophagy defects can produce accumulation of chaperone proteins that increase the unfolded protein burden (3, 4). Select protein elimination by autophagy is also important for homeostasis. The toxicity of autophagy defects in liver is partly ameliorated by deficiency in the autophagy substrate p62, but this is not the case for the brain (5, 6). The recent revelation that autophagy is important for recycling iron complexed with ferritin through ferritinophagy may be critical for iron homeostasis in many tissues, potentially including brain (7).The accumulation of, or imbalance in, levels of some cellular components caused by autophagy defects may be indirect. For example, lipid accumulation in autophagy-deficient liver and some lung tumors can arise from defects in the autophagy of lipid droplets through lipophagy (8) or indirectly from defects in mitochondrial fatty acid oxidation (FAO) that repress lipid catabolism (9). These findings collectively demonstrate the broad effects of autophagy on cellular homeostasis at the level of substrate removal, maintenance of organelle function, and detoxification. Thus, autophagy dependence is tissue specific, not only for the general requirement for the level of autophagic activity, but also for the nature of the substrates that require autophagy-mediated elimination or recycling.Acute autophagy induction is critical for yeast and normal mammalian cells and mammals to survive starvation, which is attributed to the recycling of intracellular components into metabolic pathways (2). Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy-mediated degradation of intracellular proteins and organelles provides metabolic s...

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Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition

Cited by 131 publications

References 72 publications

DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

Die another way – non-apoptotic mechanisms of cell death

The role for autophagy in cancer

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