Autophagy in malignant transformation and cancer progression

Galluzzi, Lorenzo; Pietrocola, Federico; Pedro, José Manuel Bravo-San; Amaravadi, Ravi K.; Baehrecke, Eric H.; Cecconi, Francesco; Codogno, Patrice; Debnath, Jayanta; Gewirtz, David A.; Karantza, Vassiliki; Kimmelman, Alec C.; Kumar, Sharad; Levine, Beth; Maiuri, Maria Chiara; Martin, Séamus J.; Penninger, Josef; Piacentini, Mauro; Rubinsztein, David C.; Simon, Hans Uwe; Simonsen, Anne; Thorburn, Andrew; Velasco, Guillermo; Ryan, Kevin M.; Kroemer, Guido

doi:10.15252/embj.201490784

Cited by 1,032 publications

(963 citation statements)

References 284 publications

(400 reference statements)

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“…today's consensus is that autophagy is a response to stress or damage. [63][64][65][66][67] Activation of autophagy serves to eliminate the damaged material and to generate extra energy, allowing a cell to survive a hopefully transient stress. If, in spite of this protection, the cell is too greatly stressed, it will undergo apoptosis.…”

Section: Open Questionsmentioning

confidence: 99%

Programmed cell death 50 (and beyond)

Lockshin

2015

Cell Death Differ

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In the 50 years since we described cell death as 'programmed,' we have come far, thanks to the efforts of many brilliant researchers, and we now understand the mechanics, the biochemistry, and the genetics of many of the ways in which cells can die. This knowledge gives us the resources to alter the fates of many cells. However, not all cells respond similarly to the same stimulus, in either sensitivity to the stimulus or timing of the response. Cells prevented from dying through one pathway may survive, survive in a crippled state, or die following a different pathway. To fully capitalize on our knowledge of cell death, we need to understand much more about how cells are targeted to die and what aspects of the history, metabolism, or resources available to individual cells determine how each cell reaches and crosses the threshold at which it commits to death.

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Section: Open Questionsmentioning

confidence: 99%

Programmed cell death 50 (and beyond)

Lockshin

2015

Cell Death Differ

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“…4 Studies have shown that autophagy plays different or even opposite roles depending on the cancer type and the stage of tumor progression. Currently, it is generally accepted that autophagy behaves as a tumor suppressor in normal cells in part because it removes damaged cellular components.…”

Section: * S Supporting Informationmentioning

confidence: 99%

N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy

Willett

Williams

et al. 2016

ACS Med. Chem. Lett.

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Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure−activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae. Therefore, N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides may represent a new class of autophagy modulators that possesses potent anticancer activity and potentially a novel mechanism of action.KEYWORDS: Autophagy, autophagy modulator, mTOR, pancreatic cancer, anticancer agents M acroautophagy (hereafter referred to as autophagy) is a conserved cellular process through which cytosolic components, such as proteins and organelles, are sequestered, degraded, and recycled. 1 The autophagy machinery requires a number of autophagy-related (Atg) proteins and functional complexes, including the UNC51-like kinase 1 (ULK1) complex, the class III phosphoinositide 3-kinase (PI3K) complex, the Atg12-Atg5-Atg16 ubiquitin-like conjugation system, and the microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine (PE) conjugation system. Among these autophagy components, LC3-II, which is the PE lipidated form of LC3-I, plays a key role. LC3-II is generated after a series of processing by the Atg4-Atg7-Atg3 conjugation machinery. Since it is closely involved in autophagy, the level of LC3-II is commonly used as a marker to monitor autophagy. 2 Autophagy is regulated by a network of complex signaling pathways, where the class I phosphatidylinositol 3-kinase-AKTmammalian target of rapamycin complex 1 (PI3K-AKTmTORC1) pathway is a well-established negative regulator. While a basal level of autophagy is required to maintain cellular homeostasis, it is upregulated in response to lack of nutrients, unfavorable energy status, attenuated growth signaling, virus/ bacteria invasion, and a number of cellular stresses including endoplasmic reticulum stress, oxidative stress, and hypoxia. 3 Activation of autophagy is generally accomplished by inhibiting mTORC1, which in turn increases autophagy by unblocking ULK1. In addition to its role in autophagy, mTORC1 also phosphorylates and regulates substrates including ribosomal protein S6 kinase beta-1 (P70S6K1, hereafter referred to as P70) and 4E-binding protein 1 (4EBP1), and levels of phosphorylated substrates are routinely used to gauge mTORC1 activity.The precise role of autophagy in tumorigenesis and cancer therapy still remains to be defined due to the heterogeneous nature of cancers and the complexity of the autophagy machinery. 4 Studies have shown that autophagy plays different or even opposite roles depending on the cancer type and the stage of tumor progression. Currently, it is ...

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“…31 Autophagy is inhibited by oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) via activation of the PI3K/AKT/mTORC1 and RAS/MAPK signalling. 37 In this respect, work from our group and others has shown that induction of autophagy upon pharmacological targeting of OncTKs/RTKs promotes survival. In turn, pharmacological inhibition of autophagy potentiates OncTK/RTK targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

et al. 2017

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The intracellular autophagic degradative pathway can play tumour suppressive or tumour promoting roles depending on the stage of tumour development. Upon starvation or targeting of oncogenic receptor tyrosine kinases (RTKs), autophagy is activated due to inhibition of PI3K/AKT/mTORC1 signalling pathway and promotes survival, suggesting that autophagy is a relevant therapeutic target in these settings.

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Autophagy in malignant transformation and cancer progression

Cited by 1,032 publications

References 284 publications

Programmed cell death 50 (and beyond)

Programmed cell death 50 (and beyond)

N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

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