NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression

Thakur, Basant Kumar; Lippka, Yannick; Dittrich, Tino; Prakash, Chandra; Skokowa, Julia; Welte, Karl

doi:10.1016/j.bbrc.2012.03.017

Cited by 23 publications

(10 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nuclear SIRT1 can deacetylate FOXO3, resulting in enhanced expression of the DNA repair Gadd45a gene but decreased expression of pro-apoptotic targets such as FasL and Bim [51], supporting the idea that SIRT1 promotes FOXO3-mediated genotoxic drug resistance and limits cell death. In agreement, it has also been reported that the FOXO3-mediated induction of Gadd45a expression can be negatively regulated by nicotinamide-phosphoribosyltransferase (NAMPT), a stress-induced protein, and SIRT1 [146]. Chemical inhibition of NAMPT or SIRT1 can result in increased FOXO3 acetylation and activity, and thereby, Gadd45a upregulation.…”

Section: Future Perspectives and Conclusionsupporting

confidence: 61%

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

Yao

Fan

Lam

2018

Seminars in Cancer Biology

182

149

View full text Add to dashboard Cite

The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors. This is owing to the involvement of FOXO3 and FOXM1 in the regulation of genes linked to crucial drug action-related cellular processes, including stem cell renewal, DNA repair, cell survival, drug efflux, and deregulated mitosis. A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as well as crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.

show abstract

Section: Future Perspectives and Conclusionsupporting

confidence: 61%

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

Yao

Fan

Lam

2018

Seminars in Cancer Biology

182

149

View full text Add to dashboard Cite

show abstract

“…This suggests that SIRT1 modulates the balance between FOXO3a-mediated stress resistance and cell termination [147]. Recently, it has also been reported that the FOXO3a-mediated induction of Gadd45a can be negatively regulated by nicotinamide-phosphoribosyltransferase (NAMPT), a stress-induced protein, and SIRT1 [149]. In agreement, chemical inhibition of NAMPT or SIRT1 knockdown can result in increased FOXO3a acetylation and Gadd45a upregulation.…”

Section: Targeting Foxo3a and Foxm1 In Dna Damage-response And Cancermentioning

confidence: 91%

Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance

Moraes¹,

Bella²,

Zona³

et al. 2016

CDT

View full text Add to dashboard Cite

FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1 is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses FOXM1 expression but also its transcriptional output. Recent research has provided novel insights into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1 axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating the expression of genes essential for DNA damage sensing, mediating, signalling and repair as well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in DNA-damaging agent therapy.

show abstract

“…In other inflammatory diseases, such as myocardial infarction, tyrosol activates FOXO3 and SIRT1, resulting in cardioprotection [114]. NAD-NAMPT pathway is shown to be involved in the FOXO3-mediated regulation of growth arrest and DNA damage-inducible gene (GADD45A) [115], implicating the role of this pathway in cigarette smoke-induced cellular senescence. A recent study has shown the role of SIRT1-FOXO3 axis in cellular adaptation to hypoxia-associated oxidative stress.…”

Section: Signaling Of Sirt1 In Regulation Of Inflammation and Cellulamentioning

confidence: 99%

Redox regulation of SIRT1 in inflammation and cellular senescence

Hwang¹,

Yao²,

Caito³

et al. 2013

Free Radical Biology and Medicine

428

341

View full text Add to dashboard Cite

Sirtuin1 (SIRT1) regulates inflammation, aging (lifespan and healthspan), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging where oxidative stress occurs. SIRT1 is regulated by a NAD+-dependent DNA repair enzyme poly(ADP-ribose)-polymerase-1 (PARP-1), and subsequent NAD+ depletion by oxidative stresses may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to post-translational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65 and FOXO3, thereby enhancing the inflammatory, pro-senescent and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox post-translational modifications of SIRT1 and its role in PARP1, NF-κB activation, FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging are discussed. Furthermore, we also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.

show abstract

NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression

Cited by 23 publications

References 23 publications

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance

Redox regulation of SIRT1 in inflammation and cellular senescence

Contact Info

Product

Resources

About