Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis

Lum, Julian J.; Bauer, Daniel E.; Kong, Mei; Harris, Marian H.; Li, Chi; Lindsten, Tullia; Thompson, Craig B.

doi:10.1016/j.cell.2004.11.046

Cited by 1,353 publications

(1,199 citation statements)

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“…Previously, it has been reported that autophagy provides growth-factor deprived cells with oxidizable substrates to compensate for the loss of nutrient uptake, and allows cells to maintain ATP production via catabolic metabolism. 15 The results of the present study are consistent with those derived from growth factor-deprived cells, although the source of substrates for the oxidative phosphorylation in the present study can only be presumed to be autophagolysosome-processed catabolized cellular components. The induction of autophagy following TMZ or Etoposide exposure resulted in a surge of ATP production rather than a sustained elevation as noted following growth-factor deprivation, although the surge in ATP levels was larger than could be induced by supplying exogenous substrates for oxidative phosphorylation.…”

Section: Discussionsupporting

confidence: 87%

“…Because it has been reported that autophagy provides mitochondria with substrates to maintain oxidative phosphorylation in the absence of growth factors, 15 we examined whether TMZ-induced autophagy could have a similar ATP-producing effect. To assess the effects of TMZ on the levels of ATP, we used a luciferin-luciferase based ATP bioluminescence method that has been described previously.…”

Section: Resultsmentioning

confidence: 99%

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DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

et al. 2006

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Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagyassociated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased nonapoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance. Autophagy is a process by which subcellular constituents are degraded in autophagosomes/autolysosomes in response to stress. 1 Whereas growth factors enhance the ability of metazoan cells to take up extracelluar nutrients and suppress autophagy, deprivation of either growth factors or extracellular nutrients leads to decreased nutrient uptake and derepression of autophagy. The catabolic autophagy process is believed to allow starving cells to support adenosine triphosphate (ATP) production and avoid cell death. 2,3 The autophagic process is regulated by both class I and class III phosphatidylinositol 3-kinase (PI3K) pathways. 2,4,5 Mammalian target of Rapamycin (mTOR) functions downstream of the class-I PI3K/Akt, and is a key negative regulator of autophagy. In this role, mTOR serves as a metabolic sensor that coordinates crosstalk between nutrient availability and autophagy. 6,7 In contrast, class III PI3K positively regulates autophagy. The formation of a preautophagosomal isolation membrane that encloses cytoplasmic cargo is positively regulated by phosphatidylinositol 3-phosphate, the products of class III PI3K phosphorylation. 4 It has also been suggested that the trafficking of autophagosomes is regulated by class III PI3Ks, 4,5 an idea supported by the observation that 3-methyladenine (3-MA), which inhibits class III PI3K activity, also inhibits autophagosome formation and is widely used as an autophagy inhibitor. 5 It is also known that autophagy is induced in cancer cells derived from tissues such as breast, colon, prostate and brain in response to a variety of anticancer therapies. 3,8 However, autophagy in response to these drugs can produce different outcomes, in some cases promoting cell adaptation and survival similar to what is seen in nutrient deprived cells, while in other cases, inducing programmed cell death type. The role of drug-induced autophagy in cell death or surv...

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

et al. 2006

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“…In contrast, Lum et al 13 showed that autophagy acts to ensure survival in IL-3 dependent Bax À/À Bak À/À cells following IL-3 withdrawal. IL-3 withdrawal downregulates surface nutrient transporters, resulting in intracellular starvation.…”

Section: Cell Death With Autophagymentioning

confidence: 93%

“…11 The importance of amino-acid production via autophagy was also shown in cultured cells. Lum et al 13 reported that IL-3-dependent cells maintain cell viability even after IL-3 withdrawal if the apoptotic pathway is blocked by knocking out both Bax and Bak, both of which are key initiators of apoptosis. Owing to the absence of IL-3 stimulation, these cells are unable to take up enough nutrients from the outside environment, but do still survive for a lengthy period of time.…”

Section: Introductionmentioning

confidence: 99%

The pleiotropic role of autophagy: from protein metabolism to bactericide

2005

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Autophagy is in principle a nonselective, bulk degradation system within cells, with a contribution to intracellular protein degradation estimated to be as large as that of the ubiquitin--proteasome system. The primary roles of autophagy are baseline turnover of intracellular proteins and organelles, production of amino acids in nutrient emergency, and regression of retired tissues. These functions guarantee rejuvenation and adaptation to adverse conditions, and even underlie dynamic processes such as development/metamorphosis. In addition, several other roles for autophagy have recently been discovered, such as presentation of endogenous antigens and degradation of invasive bacteria. This review will discuss the biological significance of autophagy from yeast to higher eukaryotes.

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“…For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18).…”

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confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis

Cited by 1,353 publications

References 45 publications

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

The pleiotropic role of autophagy: from protein metabolism to bactericide

Apoptosis and autophagy: regulatory connections between two supposedly different processes

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