Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway

Sui, Xianxian; Zhou, Jia; Cao, Shengxuan; Xu, Chen; Tang, Feng; Zhi, Xiuling; Chen, Bobin; Wang, Songmei; Li, Yin

doi:10.1186/s13046-017-0601-6

Cited by 21 publications

(18 citation statements)

References 56 publications

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“…There is a general enrichment of the DNA damage ATM/ATR regulation of G2/M checkpoint pathway, further strengthening the role for DNA damage and genomic instability in the disease pathogenesis [7]. Interestingly, one study provided in vitro evidence that resveratrol, a natural non-toxic phenolic compound found in the skin of grapes, produced anti-tumor effects by activating the DDR pathway in an ATM/Chk2/p53-dependent manner in ENKTL cell lines [124]. Furthermore, EBV LMP1 is known to inhibit the DDR pathways and DNA damage checkpoint activation, and may also play a role in promoting genomic instability in ENKTL [125].…”

Section: Dna Damage Repair/genome Instabilitymentioning

confidence: 99%

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

et al. 2019

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Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although l -asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the “hallmarks of cancer” as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.

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Section: Dna Damage Repair/genome Instabilitymentioning

confidence: 99%

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

et al. 2019

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“…Therefore, RSV reduces cell growth and induces apoptosis in healthy cells in a dose-dependent manner triggering biphasic effects over low to high concentrations [163,164]. For example, low-dose RSV enhances self-renewal of stem cells through inhibition of senescence whereas higher dose RSV instead inhibits self-renewal and induces senescence [165][166][167][168] through cell cycle arrest at S/G2 phase [36,169,170]. Hence, at a lower concentration, RSV can have a positive impact on the proliferation, survival of neuronal progenitor cells (NPCs), and rat hippocampal neurogenesis [167], which is also consistent with its angiogenic effects at a lower dose [94].…”

Section: Rsv Elicits Favorable and Unexpected Outcomes In Human Clinimentioning

confidence: 99%

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

2020

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Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADPribose polymerase 1 (PARP1), a major determinant of cellular NAD +-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the autopoly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention. Keywords Resveratrol (RSV). Aminoacyl-tRNA synthetases (aaRSs). Tyrosyl-tRNA synthetase (YARS. TyrRS). Nicotinamide adenine nucleotide (NAD +). Poly-ADP-ribose polymerase (PARP). Sirtuins (SIRT). AMP-activated protein kinase (AMPK). Nicotinamide (NAM) GeroScience

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“…The mechanisms proposed for resveratrol include reduced miR-155 and miR-34a expression in EBV-infected B cells along with significantly declined anti-apoptotic viral gene BHRF1 expression, thereby interfering with crucial processes implicated in EBV transformation and the survival of human EBV-transformed cells ( 66 ). Recently, another mechanism was described in extranodal natural killer (NK)/T-cell lymphoma cell lines (NT-8, SNK-10, and SNT-16), resting on the curtailment of AKT and Stat3 phosphorylation, as well as activated DNA damage response and Zta upregulation of EBV, knowing that Zta induces EBV into lytic phase and viral replication ( 207 ). However, clinical trials are required to determine whether resveratrol alone or combined with available treatments could constitute a definite advantage to combat EBV-related cancers (i.e., Hodgkin’s lymphoma, Burkitt’s lymphoma, and diffuse large B-cell lymphoma, nasopharyngeal carcinoma).…”

Section: Antiviral Activities Of Polyphenolsmentioning

confidence: 99%

Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?

Lévy

Delvin

Marcil

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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Much more serious than the previous severe acute respiratory syndrome (SARS) coronavirus (CoV) outbreaks, the novel SARS-CoV-2 infection has spread speedily, affecting 213 countries and causing ~17,300,000 million cases and ~672,000 (~+1500/day) deaths globally (as of July 31th, 2020). The potentially fatal COVID-19, caused by air droplets and airborne as the main transmission modes, clearly induces a spectrum of respiratory clinical manifestations, but it also affects the immune, gastrointestinal, hematological, nervous and renal systems. The dramatic scale of disorders and complications arise from the inadequacy of current treatments, absence of a vaccine and specific anti-COVID-19 drugs to suppress viral replication, inflammation and additional pathogenic conditions. This highlights the importance of understanding the SARS-CoV-2 mechanisms of actions, and the urgent need of prospecting for new or alternative treatment options. The main objective of the present review is to discuss the challenging issue relative to the clinical utility of plants-derived polyphenols in fighting viral infections. Not only is the strong capacity of polyphenols highlighted in magnifying health benefits, but also the underlying mechanisms are stressed. Finally, emphasis is placed on the potential ability of polyphenols to combat SARS-CoV-2 infection via the regulation of its molecular targets of human cellular binding and replication, as well as through the resulting host inflammation, oxidative stress and signalling pathways.

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Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway

Cited by 21 publications

References 56 publications

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?

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