Last update 01 Nov 2024

TIGAR

Last update 01 Nov 2024

Basic Info

Synonyms

C12orf5, Fructose-2,6-bisphosphatase TIGAR, TIGAR

+ [3]

Introduction

Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate (PubMed:19015259). Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production (PubMed:16839880, PubMed:22887998). Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death (PubMed:16839880, PubMed:19713938, PubMed:23726973, PubMed:22887998, PubMed:23817040). Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity (PubMed:23185017). In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage (By similarity). Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation (PubMed:23726973). Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions (By similarity). Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner (PubMed:22887998). Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses (PubMed:25928429). Involved in intestinal tumor progression (PubMed:23726973).

Drugs associated with TIGAR

SOT302

Target

GOT2 x TIGAR

Mechanism

GOT2 modulators [+1]

Active Org.-

Originator Org.

Sotio Biotech AS

Active Indication-

Inactive Indication-

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TIGAR

100 Translational Medicine associated with TIGAR

0 Patents (Medical) associated with TIGAR

382

Literatures (Medical) associated with TIGAR

01 Dec 2024·Molecular and Cellular Endocrinology

TIGAR relieves PCOS by inhibiting granulosa cell apoptosis and oxidative stress through activating Nrf2

Article

Author: Zhang, Jianfang ; Li, Yan ; Bai, Lu ; Wang, Haixu ; Wang, Yunping ; Xu, Jia ; Song, Hui

This study aimed to elucidate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in polycystic ovary syndrome (PCOS). A rat model PCOS was constructed by subcutaneous injection with dehydroepiandrosterone (DHEA). Follicular atresia and reduced granular cells (GCs) in ovaries suggested successful modeling. The low expression of TIGAR was observed in ovarian tissue of PCOS rat. To explore the role of TIGAR in PCOS, lentivirus carrying the TIGAR were used to up-regulate TIGAR expression. TIGAR overexpression reduced the DHEA-induced increase of ovarian weight, the levels of estradiol (E2), and the ratio of luteinizing hormone/follicle-stimulating hormone (LH/FSH) in the serum, as well as improved the morphology of the follicle, especially increased the thickness of the GC layer, which attributed to the inhibition of apoptosis by TIGAR. In addition, high expression of TIGAR inhibited oxidative stress in ovaries of PCOS rat, as evidenced by decreased level of malondialdehyde (MDA), and reactive oxygen species (ROS), and enhanced activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD). Mechanically, Nrf2/OH-1 signal pathway was activated by TIGAR. The effect of TIGAR on PCOS were verified in the primary rat GCs treated with dihydrotestosterone, but also the rescue experiment was performed. Downregulation of Nrf2 reversed the effects of TIGAR, indicating that TIGAR suppressed oxidative stress and GC apoptosis by activating Nrf2/OH-1 pathway in PCOS. Finally, non-targeted metabolomics revealed that TIGAR might affect the energy metabolic pathway, thereby altering the metabolic profile of primary rat GCs. This study provided new insights into the prevention and treatment of PCOS.

02 Aug 2024·Autophagy

TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes

Article

Author: Wu, Junchao ; Linghu, Ke-Gang ; Guo, Bing ; Chen, Diao ; Wang, Mingming ; Liu, Lirong ; Tang, Lei ; Zhou, Yuxia ; Qin, Zheng-Hong ; Shen, Yan ; Shi, Mingjun ; Tan, Jia ; Zhang, Tian

Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR^+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR^+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR^+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR^+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.

30 Jul 2024·Open Medicine

Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator

Article

Author: Ma, Tianyi ; Qiu, Lingbing ; Chen, Jugao ; Guo, Yunmiao

AbstractObjectiveThis study aims to address the substantive issue of lacking reliable prognostic biomarkers in hepatocellular carcinoma (HCC) by investigating the relationship between TP53-inducible glycolysis and apoptosis regulator (TIGAR) and HCC prognosis using The Cancer Genome Atlas database.Methods(1) Integrated statistical analyses, including logistic regression, Wilcoxon signed-rank test, and Kruskal–Wallis test, were conducted to explore the association between TIGAR expression and clinical–pathological features of HCC. (2) The Kaplan–Meier method combined with univariate and multivariate Cox regression models underscored TIGAR as a prognostic factor in HCC. (3) Gene set enrichment analysis (GSEA) revealed key pathways associated with TIGAR, while single-sample gene set enrichment analysis (ssGSEA) determined its relevance to cancer immune infiltration.Results(1) Elevated TIGAR expression was significantly correlated with decreased survival outcomes in HCC patients. (2) GSEA highlighted the significant link between TIGAR and humoral immunity. (3) ssGSEA revealed a positive correlation between TIGAR expression and infiltration of Th1 and Th2 cells and a negative correlation with Th17 cell infiltration.ConclusionTIGAR, as a potential prognostic biomarker for HCC, holds significant value in immune infiltration. Understanding the role of TIGAR could contribute to improved prognostic predictions and personalized treatment strategies for HCC patients.

News (Medical) associated with TIGAR

12 Mar 2024

·www.biospace.com

SOTIO Presents New Preclinical Data on Enhanced CAR T-Cell Therapies at AACR Annual Meeting

PRAGUE & BOSTON--(BUSINESS WIRE)-- SOTIO Biotech, a clinical-stage immuno-oncology company owned by PPF Group, today announced it will present new preclinical data at the American Association for Cancer Research (AACR) Annual Meeting taking place April 5-10, 2024, in San Diego, California. In a poster at the conference, SOTIO will present data from the company’s BOXR platform of enhanced T cell therapies. SOTIO leveraged the BOXR technology to design CAR T cells enhanced with transgenes encoding GOT2 (glutamine oxaloacetate transaminase) and TIGAR (TP53-induced glycolysis and apoptosis regulator), both of which are believed to play a role in T cell fitness in the hostile solid tumor microenvironment. Compared to unmodified CAR T cells and CAR T cells enhanced with GOT2 solely, CAR T cells enhanced with GOT2 and TIGAR showed better tumor infiltration, lower levels of exhaustion, and superior anti-tumor activity in a mouse model of solid tumors. SOTIO’s lead candidate from the BOXR platform, BOXR1030 — a GOT2-enhanced CAR T-cell therapy — is currently being evaluated in a Phase 1/2 study for patients with solid tumors. A second study to be presented at the meeting investigated the immunostimulatory effects of PARP inhibitors in models of epithelial ovarian cancer, determining their activity on molecular and cellular pathways to inform better combination therapy strategies with cancer immunotherapies. Poster details are as follows: Title: “Dual expression of exogenous glutamine oxaloacetate transaminase (GOT2) and TP53-induced glycolysis and apoptosis regulator (TIGAR) enhance CAR T cell activity in preclinical solid tumor models” Presenting Author: Amy Jensen-Smith Abstract Number: 4012 Date & Time: April 9, 2024, 9:00 a.m. – 12:30 p.m. PT Title: “Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian carcinoma” Presenting Author: Peter Holicek Abstract Number: 5278 Date & Time: April 9, 2024, 1:30 p.m. – 5:00 p.m. PT Presentation materials will be available after presentations conclude here. About SOTIO Biotech SOTIO Biotech (SOTIO) is shaping the future of cancer immunotherapies by translating compelling science into patient benefit. The SOTIO pipeline includes SOT102, a next-generation Claudin-18.2-targeted antibody-drug conjugate which entered the clinic in 2022; BOXR1030, a metabolically-enhanced CAR-T cell therapy targeting GPC3-expressing tumors as well as other molecules approaching clinical stage such as SOT201, our next-generation PD-1-inhibiting immunocytokine. SOTIO is a member of the PPF Group. For more information, please visit the company’s website at . SOTIO is a registered trademark of SOTIO Biotech a.s. in selected countries.

ImmunotherapyAACRCell Therapy

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