Autophagy in the Pathogenesis of Disease

Levine, Beth; Kroemer, Guido

doi:10.1016/j.cell.2007.12.018

Cited by 6,308 publications

(5,758 citation statements)

References 100 publications

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“…30 In the context of cancer, autophagy induction may have oncopreventive and improve therapeutic outcome after chemotherapy effects. 18,19,31–33 In addition, starvation, which is one of the best-known inducers of autophagy, increases the resistance of mice against the toxic effects of anthracycline-based chemotherapy at the same time that it improves tumor growth reduction.…”

Section: Resultsmentioning

confidence: 99%

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

et al. 2018

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The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

et al. 2018

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“…Studies have demonstrated that the antisenescence effects of AMPK are closely involved in the induction of autophagy (Levine & Kroemer, 2008; Salminen & Kaarniranta, 2012), and the physiological aging process is associated with a decline in the efficiency of autophagic degradation, which occurs in autolysosomes and largely limits autophagic flux (Mijaljica et al ., 2010). Despite the fact that the number of autophagosomes increased in senescent cells, our result strongly supports the notion that autolysosomal degradation and autophagic flux were attenuated in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Dysfunctional autophagy has been observed in aging and age‐related diseases (Levine & Kroemer, 2008; Lipinski et al ., 2010). Autophagy is a homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional cellular organelles and proteins in all living cells (Mizushima et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

et al. 2016

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Summary AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress‐induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide‐induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP‐RFP‐LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD + levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD + synthesis. In addition, the mechanistic relationship of autophagic flux and NAD + synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress‐induced senescence by improving autophagic flux and NAD + homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD + homeostasis, and it is also valuable in the development of innovative strategies to combat aging.

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“…Taken together, these data increase our understanding of the molecular pathways regulating autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation. Because autophagy has been implicated in numerous diseases, a better understanding of the molecular pathways and transcription factors regulating autophagy might lead to the development of novel strategies aimed at restoring autophagy levels in the context of disease, for example therapies targeting EGR1 expression [51]. …”

Section: Discussionmentioning

confidence: 99%

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

et al. 2018

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Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

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Autophagy in the Pathogenesis of Disease

Cited by 6,308 publications

References 100 publications

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

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Autophagy in the Pathogenesis of Disease

Cited by 6,308 publications

References 100 publications

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

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AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation