An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation

Lui, Vivian Wai Yan; Lau, Condon; Cheung, Catherine; Ho, Kwok W.; Ng, Margaret H.L.; Cheng, Suk Hang; Hong, Bo; Tsao, Sai Wah; Tsang, Chi Man; Lei, Kenny I.K.; Yamasaki, Yasundo; Mita, Akira; Chan, Anthony T.C.

doi:10.1016/j.bcp.2010.02.012

Cited by 24 publications

(18 citation statements)

References 29 publications

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“…This may provide an explanation for TIGAR activation and glycolytic inhibition in this setting, modulating metabolism and thus reducing oxidative stress in PSTs under mild ischemic conditions. These data are consistent with those previously reported in different cells, where TIGAR activation functioned to limit ROS, with protection against ROS-induced cell death (3,27,49,54,55).…”

Section: Discussionsupporting

confidence: 94%

TIGAR regulates glycolysis in ischemic kidney proximal tubules

Kim

Devalaraja-Narashimha

Padanilam

2015

American Journal of Physiology-Renal Physiology

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Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53-dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism.

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Section: Discussionsupporting

confidence: 94%

TIGAR regulates glycolysis in ischemic kidney proximal tubules

Kim

Devalaraja-Narashimha

Padanilam

2015

American Journal of Physiology-Renal Physiology

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“…Other studies have reported that decreases in GSH levels in response to modifications of the glycolytic flux could enhance radiosensitivity of U87MG cells [45], supporting the results obtained in our study. Recently a new anti-tumor molecule has been associated with the downregulation of TIGAR [19]. We have demonstrated that TI-GAR is upregulated in U87MG glioblastoma cells after radiotherapy treatment.…”

Section: Discussionmentioning

confidence: 81%

“…A recent study has revealed that enhanced PPP and increased antioxidant capacity correlate with metastasis of breast cancer cells to the brain [18]. In addition, recent findings have demonstrated that an anticancer molecule mediates its effects via TIGAR downregulation associated with a decrease in NADPH levels [19]. In the present study, we look at the TIGAR knockdown effects in glioma U87MG and T98G cells and analyze its potential therapeutic utility as an enhancer of radiotherapy action in glioblastoma derived cell-lines.…”

Section: Introductionmentioning

confidence: 91%

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells

Peña‐Rico¹,

Calvo-Vidal²,

Villalonga-Planells³

et al. 2011

Radiotherapy and Oncology

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a b s t r a c tBackground and purpose: The TP53 induced glycolysis and apoptosis regulator (TIGAR) functions to lower fructose-2,6-bisphosphate (Fru-2,6-P 2 ) levels in cells, consequently decreasing glycolysis and leading to the scavenging of reactive oxygen species (ROS), which correlate with a higher resistance to cell death. The decrease in intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic lesions. Given these good prospects of TIGAR for metabolic regulation and p53-response modulation, we analyzed the effects of TIGAR knockdown in U87MG and T98G glioblastoma-derived cell lines. Methods/results: After TIGAR-knockdown in glioblastoma cell lines, different metabolic parameters were assayed, showing an increase in Fru-2,6-P 2 , lactate and ROS levels, with a concomitant decrease in reduced glutathione (GSH) levels. In addition, cell growth was inhibited without evidence of apoptotic or autophagic cell death. In contrast, a clear senescent phenotype was observed. We also found that TIGAR protein levels were increased shortly after irradiation. In addition, avoiding radiotherapy-triggered TIGAR induction by gene silencing resulted in the loss of capacity of glioblastoma cells to form colonies in culture and the delay of DNA repair mechanisms, based in c-H2AX foci, leading cells to undergo morphological changes compatible with a senescent phenotype. Thus, the results obtained raised the possibility to consider TIGAR as a therapeutic target to increase radiotherapy effects. Conclusion: TIGAR abrogation provides a novel adjunctive therapeutic strategy against glial tumors by increasing radiation-induced cell impairment, thus allowing the use of lower radiotherapeutic doses.

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“…Lui and colleagues demonstrated that TIGAR/NADPH cascade was involved in antitumor effects of a new c-Met tyrosine kinase inhibitor, suggesting that inhibition of TIGAR may have an antitumor potentiality (25). ECyd, an RNA-directed nucleoside anti-metabolite, elicits its antitumor effect via TIGAR downregulation (26).…”

Section: Discussionmentioning

confidence: 99%

TIGAR Has a Dual Role in Cancer Cell Survival through Regulating Apoptosis and Autophagy

Xie

et al. 2014

Cancer Research

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The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose-and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127-38. Ó2014 AACR.

show abstract

An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation

Cited by 24 publications

References 29 publications

TIGAR regulates glycolysis in ischemic kidney proximal tubules

TIGAR regulates glycolysis in ischemic kidney proximal tubules

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells

TIGAR Has a Dual Role in Cancer Cell Survival through Regulating Apoptosis and Autophagy

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