The Tumor Suppressor PTEN Positively Regulates Macroautophagy by Inhibiting the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Arico, Sébastien; Petiot, Anne; Bauvy, Chantal; Dubbelhuis, Peter F.; Meijer, Alfred J.; Codogno, Patrice; Ogier–Denis, Éric

doi:10.1074/jbc.c100319200

Cited by 531 publications

(447 citation statements)

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“…In tumorigenesis, the signaling control of autophagy may depend upon the activity of tumor suppressor genes such as PTEN in colon cancer cells and Beclin-1 in breast cancer cells. 33,34 Recent investigations suggest that autophagy plays a defensive role in cancer therapy. 15,35 In general, autophagic degradation is reduced in cancer cells than in their normal counterparts.…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 lM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein lightchain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H þ -ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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Section: Discussionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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“…27 Indeed, overexpression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which removes the phosphate from the 3-position of PI(3,4)P 2 and PI(3,4,5)P 3 , increases autophagy. 28 The PI3K inhibitors do not distinguish between class-I and -III PI3K, and also inhibit the formation of PI(3)P, and thus inhibit autophagy. 3-Methyladenine (3-MA), the specific inhibitor of autophagy, turned out to be an inhibitor of PI3K, which explains why it has an inhibitory effect on both autophagy and S6 phosphorylation.…”

Section: Inhibition Of Autophagy By Amino Acidsmentioning

confidence: 99%

“…In support of the scheme depicted in Figure 1, it has been found that overexpression of PKB inhibits autophagy, whereas expression of the dominant-negative PKB greatly stimulates the process. 28 Although autophagy is negatively controlled by mTOR activity, the suggestion that the inhibition of autophagy by amino acids also proceeds via mTOR has been challenged.…”

Section: Inhibition Of Autophagy By Amino Acidsmentioning

confidence: 99%

Autophagy and signaling: their role in cell survival and cell death

2005

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Macroautophagy is a vacuolar, self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by the lysosome. The discovery of the ATG genes has provided key information about the formation of the autophagosome, and about the role of macroautophagy in allowing cells to survive during nutrient depletion and/or in the absence of growth factors. Two connected signaling pathways encompassing class-I phosphatidylinositol 3-kinase and (mammalian) target of rapamycin play a central role in controlling macroautophagy in response to starvation. However, a considerable body of literature reports that macroautophagy is also a cell death mechanism that can occur either in the absence of detectable signs of apoptosis (via autophagic cell death) or concomitantly with apoptosis. Macroautophagy is activated by signaling pathways that also control apoptosis. The aim of this review is to discuss the signaling pathways that control macroautophagy during cell survival and cell death.

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“…For example, p53, which is a potent inducer of apoptosis, can also induce autophagy through increased expression of a direct p53 target gene called DRAM (67). Similarly activation of the PI3 kinase/ Akt pathway, which is a well known way to inhibit apoptosis, also inhibits autophagy (68). Thus important signaling pathways apparently simultaneously increase or decrease both autophagy and apoptosis.…”

Section: Molecular Connections Between Autophagy and Apoptosismentioning

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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The Tumor Suppressor PTEN Positively Regulates Macroautophagy by Inhibiting the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Cited by 531 publications

References 40 publications

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Autophagy and signaling: their role in cell survival and cell death

Apoptosis and autophagy: regulatory connections between two supposedly different processes

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