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
Autophagyjournal_title
Autophagyauthors
Wang Y,Hu Z,Liu Z,Chen R,Peng H,Guo J,Chen X,Zhang Hdoi
10.4161/auto.26447subject
Has Abstractpub_date
2013-12-01 00:00:00pages
2069-86issue
12eissn
1554-8627issn
1554-8635pii
26447journal_volume
9pub_type
杂志文章相关文献
Autophagy文献大全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
更新日期:2016-11-01 00:00:00
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
更新日期:2020-10-01 00:00:00
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
更新日期:2017-08-03 00:00:00
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
更新日期:2006-10-01 00:00:00
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
更新日期:2008-07-01 00:00:00
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
更新日期:2011-08-01 00:00:00
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
更新日期:2010-04-01 00:00:00
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
更新日期:2016-10-02 00:00:00
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
更新日期:2020-12-07 00:00:00
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
更新日期:2020-01-01 00:00:00
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
更新日期:2018-01-01 00:00:00
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
更新日期:2014-08-01 00:00:00
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
更新日期:2017-05-04 00:00:00
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
更新日期:2015-11-02 00:00:00
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
更新日期:2009-10-01 00:00:00
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
更新日期:2012-11-01 00:00:00
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
更新日期:2019-09-01 00:00:00
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
更新日期:2016-09-01 00:00:00
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
更新日期:2019-06-01 00:00:00
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
更新日期:2017-08-03 00:00:00
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
更新日期:2017-10-03 00:00:00
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
更新日期:2019-01-01 00:00:00
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
更新日期:2009-11-01 00:00:00
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
更新日期:2020-08-01 00:00:00
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
更新日期:2007-03-01 00:00:00
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
更新日期:2010-10-01 00:00:00
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
更新日期:2019-08-01 00:00:00
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
更新日期:2016-10-02 00:00:00
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
更新日期:2013-06-01 00:00:00
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
更新日期:2012-03-01 00:00:00