Reciprocal regulation of autophagy and dNTP pools in human cancer cells

Chen, Wei; Zhang, Lisheng; Zhang, Keqiang; Zhou, Bingsen; Kuo, Mei Ling; Hu, Shuya; Chen, Linling; Tang, Michelle; Chen, Yun‐Ru; Yang, Lixin; Ann, David K.; Yen, Yun

doi:10.4161/auto.28954

Cited by 54 publications

(40 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following starvation, autophagy is induced to recycle cellular components and supply building blocks for metabolic pathways [62]. Indeed, autophagy-deficient cells accumulate DNA damage, presumably by excessive degradation of checkpoint proteins [9] or perhaps by deregulated dNTP metabolism [63]. From the disease relevance point of view, our present results support the view that autophagy can support tumour progression, at least in part by responding to oncogene-or genotoxic therapyinduced RS that stimulates autophagy flux.…”

Section: Discussionsupporting

confidence: 73%

Autophagy role(s) in response to oncogenes and DNA replication stress

et al. 2019

View full text Add to dashboard Cite

Autophagy is an evolutionarily conserved process that captures aberrant intracellular proteins and/or damaged organelles for delivery to lysosomes, with implications for cellular and organismal homeostasis, aging and diverse pathologies, including cancer. During cancer development, autophagy may play both tumour-supporting and tumour-suppressing roles. Any relationships of autophagy to the established oncogene-induced replication stress (RS) and the ensuing DNA damage response (DDR)-mediated anti-cancer barrier in early tumorigenesis remain to be elucidated. Here, assessing potential links between autophagy, RS and DDR, we found that autophagy is enhanced in both early and advanced stages of human urinary bladder and prostate tumorigenesis. Furthermore, a high-content, single-cell-level microscopy analysis of human cellular models exposed to diverse genotoxic insults showed that autophagy is enhanced in cells that experienced robust DNA damage, independently of the cell-cycle position. Oncogene-and drug-induced RS triggered first DDR and later autophagy. Unexpectedly, genetic inactivation of autophagy resulted in RS, despite cellular retention of functional mitochondria and normal ROS levels. Moreover, recovery from experimentally induced RS required autophagy to support DNA synthesis. Consistently, RS due to the absence of autophagy could be partly alleviated by exogenous supply of deoxynucleosides. Our results highlight the importance of autophagy for DNA synthesis, suggesting that autophagy may support cancer progression, at least in part, by facilitating tumour cell survival and fitness under replication stress, a feature shared by most malignancies. These findings have implications for better understanding of the role of autophagy in tumorigenesis, as well as for attempts to manipulate autophagy as an anti-tumour therapeutic strategy.

show abstract

Section: Discussionsupporting

confidence: 73%

Autophagy role(s) in response to oncogenes and DNA replication stress

et al. 2019

View full text Add to dashboard Cite

show abstract

“…This suggests that ATRA induces CCR5 expression via mTOR-independent mechanisms and that mTOR regulation of HIV permissiveness in gut-homing CD4 + T cells likely occurs at postentry levels. Consistent with the evidence that mTOR regulates nucleotide biosynthesis essential for transcription (76,80,81), mTOR inhibitors may limit HIV reverse transcription by reducing the pool of nucleotides. Indeed, our single-round infection using VSV-Gpseudotyped HIV revealed restriction mechanisms acting during reverse transcription and prior to integration.…”

Section: On Hiv Replication In Ccr6mentioning

confidence: 54%

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

Planas¹,

Zhang²,

Monteiro³

et al. 2017

JCI Insight

161

View full text Add to dashboard Cite

“…Despite upregulation of autophagy has widely been shown to promote DNA repair in cells treated with different DNA damaging agents [48][49][50], other studies revealed that excessive autophagy could induce genomic instability in cancer cells. For example, excessive autophagy has been shown to decrease the activity of ribonucleotide reductase and the production of deoxyribonucleoside triphosphates (dNTPs), leading to the induction of genomic instability in human cancer cells [51,52]. Furthermore, Huang et al demonstrated that targeting CTSS (cathepsin S) by small molecule inhibitors induced autophagy-dependent ROS production and the ROS-dependent DNA damage in HONE-1 cells [53].…”

Section: Discussionmentioning

confidence: 99%

BIRC5/Survivin is a novel ATG12–ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells

et al. 2019

View full text Add to dashboard Cite

2020) BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells, Autophagy, 16:7, 1296-1313, ABSTRACT BIRC5/Survivin is known as a dual cellular functions protein that directly regulates both apoptosis and mitosis in embryonic cells during embryogenesis and in cancer cells during tumorigenesis and tumor metastasis. However, BIRC5 has seldom been demonstrated as a direct macroautophagy/autophagy regulator in cells. ATG7 expression and ATG12-ATG5-ATG16L1 complex formation are crucial for the phagophore elongation during autophagy in mammalian cells. In this study, we observed that the protein expression levels of BIRC5 and ATG7 were inversely correlated, whereas the expression levels of BIRC5 and SQSTM1/p62 were positively correlated in normal breast tissues and tumor tissues. Mechanistically, we found that BIRC5 negatively modulates the protein stability of ATG7 and physically binds to the ATG12-ATG5 conjugate, preventing the formation of the ATG12-ATG5-ATG16L1 protein complex in human cancer (MDA-MB-231, MCF7, and A549) and mouse embryonic fibroblast (MEF) cells. We also observed a concurrent physical dissociation between BIRC5 and ATG12-ATG5 (but not CASP3/caspase-3) and upregulation of autophagy in MDA-MB-231 and A549 cells under serum-deprived conditions. Importantly, despite the fact that upregulation of autophagy is widely thought to promote DNA repair in cells under genotoxic stress, we found that BIRC5 maintains DNA integrity through autophagy negative-modulations in both human cancer and MEF cells under non-stressed conditions. In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a "bridging molecule", which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells.

show abstract

Reciprocal regulation of autophagy and dNTP pools in human cancer cells

Cited by 54 publications

References 38 publications

Autophagy role(s) in response to oncogenes and DNA replication stress

Autophagy role(s) in response to oncogenes and DNA replication stress

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

BIRC5/Survivin is a novel ATG12–ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells

Contact Info

Product

Resources

About