Metabolic alterations accompanying oncogene-induced senescence

Aird, Katherine M.; Zhang, Rugang

doi:10.4161/23723548.2014.963481

Cited by 32 publications

(29 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This DDR checkpoint decline in subsets of advanced cancers reflects events, such as selection for loss-of-function mutations in the ATM-Chk2 signalling module that activates p53, or selection for mutations in the p53 tumour suppressor itself [17]. Our data also challenge the belief that autophagy might be activated exclusively to promote cellular senescence [46], a known tumour-suppressive mechanism, as we observed increased autophagy flux also in models, in which senescence is not induced by oncogenic activation (Fig. S3).…”

Section: Discussionmentioning

confidence: 56%

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: Discussionmentioning

confidence: 56%

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

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Further understanding of the age groups comparable between laboratory senescence [72,73]. Furthermore, oncogene-induced senescence results in metabolic alterations including elevated acetyl-CoA levels and TCA cycle activity [74]. Taking these findings together, a biphasic model in which mitochondrial activity is increased in middle-age may support the induction of chronic senescence in middle-age and therefore negatively impact healthy lifespan.…”

Section: Box 1 Translating Survival Curves From Animal Models To Humansmentioning

confidence: 97%

Biphasic Modeling of Mitochondrial Metabolism Dysregulation during Aging

Baker

Peleg

2017

Trends in Biochemical Sciences

View full text Add to dashboard Cite

Organismal aging is classically viewed as a gradual decline of cellular functions and a systemic deterioration of tissues that leads to an increased mortality rate in older individuals. According to the prevailing theory, aging is accompanied by a continuous and progressive decline in mitochondrial metabolic activity in cells. However, the most robust approaches to extending healthy lifespan are frequently linked with reduced energy intake or with lowering of mitochondrial activity. While these observations appear contradictory, recent work and technological advances demonstrate that metabolic deregulation during aging is potentially biphasic. In this Opinion we propose a novel framework where middle-age is accompanied by increased mitochondrial activity that subsequently declines at advanced ages.

show abstract

“…This lack of concerted metabolic reprogramming can lead to over-reliance on certain metabolic pathway and substrates, and the need for damage control mechanisms. Indeed, aberrant activation of oncogenes such as Myc and Ras can lead to oncogene-induced cellular senescence and downregulation of anabolic pathways - a hurdle that cancer cells must overcome for tumorigenesis (Aird and Zhang, 2014). The recognition that cellular stress pathways enable cancer cell survival in response to nutrient depletion and hypoxia in the tumor microenvironment has fueled the development of drugs targeting these pathways (Luo et al, 2009).…”

Section: Metabolic Plasticity and Stress In Cancermentioning

confidence: 99%

Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors

2017

View full text Add to dashboard Cite

Summary It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype is not unique to cancer cells but instead reflects characteristics of proliferating cells. Similar metabolic transitions also occur in the immune system as cells transition from resting state to stimulated effectors. A key finding in immune metabolism is that the metabolic programs of different cell subsets are distinctly associated with immunological function. Further, interruption of those metabolic pathways can shift immune cell fate to modulate immunity. These studies have identified numerous metabolic similarities between cancer and immune cells, but also critical differences that may be exploited and affect treatment of cancer and immunological diseases.

show abstract

Metabolic alterations accompanying oncogene-induced senescence

Cited by 32 publications

References 89 publications

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

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

Biphasic Modeling of Mitochondrial Metabolism Dysregulation during Aging

Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors

Contact Info

Product

Resources

About