MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1.

Abstract:

:Hyperactivation of mechanistic target of rapamycin (MTOR) is a common feature of human cancers, and MTOR inhibitors, such as rapamycin, are thus becoming therapeutics in targeting certain cancers. However, rapamycin has also been found to compromise the efficacy of chemotherapeutics to cells with hyperactive MTOR. Here, we show that loss of TSC2 or PTEN enhanced etoposide-induced DNA damage and apoptosis, which was blunted by suppression of MTOR with either rapamycin or RNA interference. cAMP response element-binding protein 1 (CREB1), a nuclear transcription factor that regulates genes involved in survival and death, was positively regulated by MTOR in mouse embryonic fibroblasts (MEFs) and cancer cell lines. Silencing Creb1 expression with siRNA protected MTOR-hyperactive cells from DNA damage-induced apoptosis. Furthermore, loss of TSC2 or PTEN impaired either etoposide or nutrient starvation-induced autophagy, which in turn, leads to CREB1 hyperactivation. We further elucidated an inverse correlation between autophagy activity and CREB1 activity in the kidney tumor tissue obtained from a TSC patient and the mouse livers with hepatocyte-specific knockout of PTEN. CREB1 induced DNA damage and subsequent apoptosis in response to etoposide in autophagy-defective cells. Reactivation of CREB1 or inhibition of autophagy not only improved the efficacy of rapamycin but also alleviated MTOR inhibition-mediated chemoresistance. Therefore, autophagy suppression of CREB1 may underlie the MTOR inhibition-mediated chemoresistance. We suggest that inhibition of MTOR in combination with CREB1 activation may be used in the treatment of cancer caused by an abnormal PI3K-PTEN-AKT-TSC1/2-MTOR signaling pathway. CREB1 activators should potentiate the efficacy of chemotherapeutics in treatment of these cancers.

journal_name

Autophagy

journal_title

Autophagy

authors

Wang Y,Hu Z,Liu Z,Chen R,Peng H,Guo J,Chen X,Zhang H

doi

10.4161/auto.26447

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

2069-86

issue

12

eissn

1554-8627

issn

1554-8635

pii

26447

journal_volume

9

pub_type

杂志文章
  • Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase.

    abstract::Autophagy, a catabolic pathway of lysosomal degradation, acts not only as an efficient recycle and survival mechanism during cellular stress, but also as an anti-infective machinery. The human pathogen Staphylococcus aureus (S. aureus) was originally considered solely as an extracellular bacterium, but is now recogniz...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2016.1226732

    authors: Neumann Y,Bruns SA,Rohde M,Prajsnar TK,Foster SJ,Schmitz I

    更新日期:2016-11-01 00:00:00

  • Autophagic degradation of KAT2A/GCN5 promotes directional migration of vascular smooth muscle cells by reducing TUBA/α-tubulin acetylation.

    abstract::Macroautophagy/autophagy, a fundamental process for degradation of macromolecules and organelles, occurs constitutively at a basal level and is upregulated in response to stress. Whether autophagy regulates protein acetylation and microtubule stability in vascular smooth muscle cells (VSMCs) migration, however, remain...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2019.1707488

    authors: Ouyang C,Mu J,Lu Q,Li J,Zhu H,Wang Q,Zou MH,Xie Z

    更新日期:2020-10-01 00:00:00

  • Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks.

    abstract::Macroautophagy/autophagy is a dynamic and inducible catabolic process that responds to a variety of hormonal and environmental cues. Recent studies highlight the interplay of this central pathway in a variety of pathophysiological diseases. Although defective autophagy is implicated in melanocyte proliferation and pig...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2017.1327509

    authors: Ramkumar A,Murthy D,Raja DA,Singh A,Krishnan A,Khanna S,Vats A,Thukral L,Sharma P,Sivasubbu S,Rani R,Natarajan VT,Gokhale RS

    更新日期:2017-08-03 00:00:00

  • Exploiting cell death pathways by an E. coli cytotoxin: autophagy as a double-edged sword for the host.

    abstract::Cytotoxic necrotizing factor 1 is a bacterial protein toxin from Escherichia coli that is able to activate the Rho GTPases and to hinder apoptosis and mitotic catastrophe. Upon exposure to toxin, cells undergo a complex framework of changes, including cytoskeleton remodeling and multinucleation. These cells also show ...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.2965

    authors: Fiorentini C,Malorni W

    更新日期:2006-10-01 00:00:00

  • Dual role of Atg1 in regulation of autophagy-specific PAS assembly in Saccharomyces cerevisiae.

    abstract::Most autophagy-related (Atg) proteins are assembled at the phagophore assembly site or pre-autophagosomal structure (PAS), which is a potential site for vesicle formation during vegetative or starvation conditions. To understand the initial step of vesicle formation, it is important to know how Atg proteins are recrui...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.6375

    authors: Cheong H,Klionsky DJ

    更新日期:2008-07-01 00:00:00

  • Oncogene-induced autophagy and the Goldilocks principle.

    abstract::Although several oncogenes enhance autophagic flux, the molecular mechanism and consequences of oncogene-induced autophagy remain to be clarified. We have recently shown that expression of oncogenic H-Ras (V12) promotes autophagy through upregulation of Beclin 1 and the BH3-only protein Noxa. H-Ras-expressing cells un...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.7.8.15821

    authors: Martin SJ

    更新日期:2011-08-01 00:00:00

  • Reticulocyte mitophagy: monitoring mitochondrial clearance in a mammalian model.

    abstract::Mitochondria are the primary site of energy production in animal cells. In mitochondria, the flow of electrons through the electron transport chain creates a potential difference across the inner membrane, which is utilized for ATP production. However, due to inherent inefficiencies in electron transport, reactive oxy...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.6.3.11245

    authors: Zhang J,Ney PA

    更新日期:2010-04-01 00:00:00

  • TBC1D20 mediates autophagy as a key regulator of autophagosome maturation.

    abstract::In humans, loss of TBC1D20 (TBC1 domain family, member 20) protein function causes Warburg Micro syndrome 4 (WARBM4), an autosomal recessive disorder characterized by congenital eye, brain, and genital abnormalities. TBC1D20-deficient mice exhibit ocular abnormalities and male infertility. TBC1D20 is a ubiquitously ex...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2016.1199300

    authors: Sidjanin DJ,Park AK,Ronchetti A,Martins J,Jackson WT

    更新日期:2016-10-02 00:00:00

  • Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5).

    abstract::Blood-brain barrier (BBB) disruption is a key event in triggering secondary damage to the central nervous system (CNS) under stroke, and is frequently associated with abnormal macroautophagy/autophagy in brain microvascular endothelial cells (BMECs). However, the underlying mechanism of autophagy in maintaining BBB in...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2020.1851897

    authors: Yang Z,Lin P,Chen B,Zhang X,Xiao W,Wu S,Huang C,Feng D,Zhang W,Zhang J

    更新日期:2020-12-07 00:00:00

  • Essential role of autophagy in resource allocation during sexual reproduction.

    abstract::Sexual reproduction is the most common form of reproduction among eukaryotes, which is characterized by a series of massive cellular or tissue renovations. Recent studies have revealed novel functions of autophagy during sexual reproductive processes, ranging from yeast to mammals. In mammals, autophagy is indispensab...

    journal_title:Autophagy

    pub_type: 杂志文章,评审

    doi:10.1080/15548627.2019.1628543

    authors: Gao H,Khawar MB,Li W

    更新日期:2020-01-01 00:00:00

  • Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression.

    abstract::Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is com...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2017.1385674

    authors: Perera ND,Sheean RK,Lau CL,Shin YS,Beart PM,Horne MK,Turner BJ

    更新日期:2018-01-01 00:00:00

  • A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

    abstract::Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnos...

    journal_title:Autophagy

    pub_type: 杂志文章,多中心研究

    doi:10.4161/auto.28984

    authors: Rosenfeld MR,Ye X,Supko JG,Desideri S,Grossman SA,Brem S,Mikkelson T,Wang D,Chang YC,Hu J,McAfee Q,Fisher J,Troxel AB,Piao S,Heitjan DF,Tan KS,Pontiggia L,O'Dwyer PJ,Davis LE,Amaravadi RK

    更新日期:2014-08-01 00:00:00

  • Autophagosome formation: Where the secretory and autophagy pathways meet.

    abstract::The upregulation of autophagosome formation in response to nutrient deprivation requires significant intracellular membrane rearrangements that are poorly understood. Recent findings have implicated COPII-coated vesicles, well known as ER-Golgi cargo transport carriers, as key players in macroautophagy. The role of CO...

    journal_title:Autophagy

    pub_type: 杂志文章,评审

    doi:10.1080/15548627.2017.1287657

    authors: Wang J,Davis S,Zhu M,Miller EA,Ferro-Novick S

    更新日期:2017-05-04 00:00:00

  • Disease relevance of phosphorylated ubiquitin (p-S65-Ub).

    abstract::Here, we present a summary of our recent findings on the (patho-)physiological relevance of PINK1-phosphorylated ubiquitin (p-S65-Ub). Using novel polyclonal antibodies, we find that p-S65-Ub specifically accumulates on damaged mitochondria. Phosphorylation of ubiquitin on serine 65 depends on the activity of PINK1 an...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2015.1091912

    authors: Fiesel FC,Springer W

    更新日期:2015-11-02 00:00:00

  • Nuclear membrane-derived autophagy, a novel process that participates in the presentation of endogenous viral antigens during HSV-1 infection.

    abstract::Complex membrane trafficking events are involved in the regulation of antigen processing and presentation of both endogenous and exogenous antigens. While these processes were believed to involve mainly organelles along the endo/phagocytic and the biosynthetic pathways, recent studies have shown that autophagy also pa...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.5.7.9163

    authors: English L,Chemali M,Desjardins M

    更新日期:2009-10-01 00:00:00

  • Recycling endosomes contribute to autophagosome formation.

    abstract::Autophagosome formation is a complex cellular process, which requires major membrane rearrangements leading to the creation of a relatively large double-membrane vesicle that directs its contents to the lysosome for degradation. Although various membrane compartments have been identified as sources for autophagosomal ...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.21486

    authors: Longatti A,Tooze SA

    更新日期:2012-11-01 00:00:00

  • The "found-art vacuole"-people learn in different ways.

    abstract::Based on my reading, and on my own experience, I have come to realize that people learn in different ways, and this can include the use of different media. This is one reason I have worked with various artists to portray the topic of autophagy through paintings, music and dance. Indeed, comments from members of the au...

    journal_title:Autophagy

    pub_type: 评论,社论

    doi:10.1080/15548627.2019.1630225

    authors: Klionsky DJ

    更新日期:2019-09-01 00:00:00

  • Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity.

    abstract::BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating ...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2016.1191723

    authors: Zhang Y,Shen K,Bai Y,Lv X,Huang R,Zhang W,Chao J,Nguyen LK,Hua J,Gan G,Hu G,Yao H

    更新日期:2016-09-01 00:00:00

  • Restoring autophagic flux attenuates cochlear spiral ganglion neuron degeneration by promoting TFEB nuclear translocation via inhibiting MTOR.

    abstract::Macroautophagy/autophagy dysfunction is associated with many neurodegenerative diseases. TFEB (transcription factor EB), an important molecule that regulates lysosomal and autophagy function, is regarded as a potential target for treating some neurodegenerative diseases. However, the relationship between autophagy dys...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2019.1569926

    authors: Ye B,Wang Q,Hu H,Shen Y,Fan C,Chen P,Ma Y,Wu H,Xiang M

    更新日期:2019-06-01 00:00:00

  • Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy.

    abstract::Oxidative stress-induced granulosa cell (GCs) death represents a common reason for follicular atresia. Follicle-stimulating hormone (FSH) has been shown to prevent GCs from oxidative injury, although the underlying mechanism remains to be elucidated. Here we first report that the suppression of autophagic cell death v...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2017.1327941

    authors: Shen M,Jiang Y,Guan Z,Cao Y,Li L,Liu H,Sun SC

    更新日期:2017-08-03 00:00:00

  • Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.

    abstract::Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritiona...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2017.1349581

    authors: Li X,Qian X,Lu Z

    更新日期:2017-10-03 00:00:00

  • Mitochondrial quality control mediated by PINK1 and PRKN: links to iron metabolism and tumor immunity.

    abstract::Mitochondrial quality control is an essential process required to maintain cellular homeostasis and functions. Mutations of PINK1 and PRKN/PARK2 contribute to the risk of Parkinson disease. Our recent findings indicate that depletion of Pink1 and Prkn promotes pancreatic tumorigenesis in KRAS-driven engineered mouse m...

    journal_title:Autophagy

    pub_type: 评论,杂志文章

    doi:10.1080/15548627.2018.1526611

    authors: Kang R,Xie Y,Zeh HJ,Klionsky DJ,Tang D

    更新日期:2019-01-01 00:00:00

  • Autophagy and access: understanding the role of androgen receptor subcellular localization in SBMA.

    abstract::Ridding neurons of toxic misfolded proteins is a critical feature of many neurodegenerative diseases. We have recently reported that lack of access of nuclear polyglutamine-expanded androgen receptor (AR) to the autophagic degradation pathway is a critical point in pathogenesis. When mutant AR is contained within the ...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.5.8.9726

    authors: Montie HL,Merry DE

    更新日期:2009-11-01 00:00:00

  • RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells.

    abstract::Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis-indu...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2019.1687985

    authors: Zhang Z,Guo M,Li Y,Shen M,Kong D,Shao J,Ding H,Tan S,Chen A,Zhang F,Zheng S

    更新日期:2020-08-01 00:00:00

  • 4th International Symposium on Autophagy: exploiting the frontiers of autophagy research.

    abstract::The 4th International Symposium on Autophagy was held in Mishima, a small town between Tokyo and Kyoto, October 1-5, 2006 (http://isa4th.umin.jp/). The meeting was organized by the group of Eiki Kominami. Approximately 150 participants took part in this well-organized meeting in the spacious and comfortable Toray Conf...

    journal_title:Autophagy

    pub_type:

    doi:10.4161/auto.3654

    authors: Eskelinen EL,Deretic V,Neufeld T,Levine B,Cuervo AM

    更新日期:2007-03-01 00:00:00

  • Autophagic degradation of an oncoprotein.

    abstract::Acute promyelocytic leukemia (APL) is characterized by a chromosomal t(15;17) translocation that fuses the gene encoding the promyelocytic leukemia protein (PML) to that encoding retinoic acid receptor alpha (RARA). The product of this genetic aberration, the PML/RARA fusion protein, is highly oncogenic and supports m...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.6.7.13066

    authors: Bøe SO,Simonsen A

    更新日期:2010-10-01 00:00:00

  • How RB1CC1/FIP200 claws its way to autophagic engulfment of SQSTM1/p62-ubiquitin condensates.

    abstract::Macroautophagy/autophagy mediates the degradation of ubiquitinated aggregated proteins within lysosomes in a process known as aggrephagy. The cargo receptor SQSTM1/p62 condenses aggregated proteins into larger structures and links them to the nascent autophagosomal membrane (phagophore). How the condensation reaction ...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2019.1615306

    authors: Turco E,Witt M,Abert C,Bock-Bierbaum T,Su MY,Trapannone R,Sztacho M,Danieli A,Shi X,Zaffagnini G,Gamper A,Schuschnig M,Fracchiolla D,Bernklau D,Romanov J,Hartl M,Hurley JH,Daumke O,Martens S

    更新日期:2019-08-01 00:00:00

  • Spatiotemporal dynamics of autophagy receptors in selective mitophagy.

    abstract::Damaged mitochondria are turned over through a process of selective autophagy termed mitophagy. In mitophagy, unhealthy mitochondria are recognized and ubiquitinated by Parkinson disease-linked proteins PINK1 and PARK2. The subsequent recruitment of ubiquitin-binding autophagy receptors leads in turn to the sequestrat...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.1080/15548627.2016.1212788

    authors: Moore AS,Holzbaur EL

    更新日期:2016-10-02 00:00:00

  • Spread of neuronal degeneration in a dopaminergic, Lrrk-G2019S model of Parkinson disease.

    abstract::Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstr...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.24397

    authors: Hindle SJ,Elliott CJ

    更新日期:2013-06-01 00:00:00

  • PKD at the crossroads of necrosis and autophagy.

    abstract::Reactive oxygen species (ROS) that accumulate under oxidative pressure cause severe damage to cellular components, and induce various cellular responses, including apoptosis, programmed necrosis and autophagy, depending on the cellular setting. Various studies have described ROS-induced autophagy, but only a few direc...

    journal_title:Autophagy

    pub_type: 杂志文章

    doi:10.4161/auto.19288

    authors: Eisenberg-Lerner A,Kimchi A

    更新日期:2012-03-01 00:00:00