Last update 01 Nov 2024

ME3

Last update 01 Nov 2024

Basic Info

Synonyms

malic enzyme 3, ME3, NADP-dependent malic enzyme, mitochondrial

+ [1]

Introduction

Catalyzes the oxidative decarboxylation of (S)-malate to pyruvate using NADP(+) as a cofactor (PubMed:7818469). Can also reverse the decarboxylation reaction, but only with significantly lower efficiency (PubMed:7818469).

Drugs associated with ME3

ME3 inhibitor (Maitong Biotechnology)

Target

ME3

Mechanism

ME3 inhibitors

Active Org.

Zhejiang Maitong Biopharmaceutical Co. Ltd.

Originator Org.

Zhejiang Maitong Biopharmaceutical Co. Ltd.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Compound 16b(Sun Pharma)

Target

ME3

Mechanism

ME3 modulators

Active Org.

Zhejiang University of Technology

Originator Org.

Sun Pharma Advanced Research Company Ltd.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ME3

100 Translational Medicine associated with ME3

0 Patents (Medical) associated with ME3

133

Literatures (Medical) associated with ME3

01 Dec 2024·Cellular and Molecular Life Sciences

Downregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxia-inducible factor-1α stabilization

Article

Author: Lv, Xiadong ; Chen, Xiangliu ; Chen, Yiran ; Hu, Xun ; Teng, Lisong ; Zeng, Siying ; Wang, Haiyong ; Yang, Yan ; Huang, Yingying

BACKGROUNDGastric cancer (GC) is one of the most malignant cancers worldwide. Metabolism disorder is a critical characteristic of malignant tumors related to tumor progression and metastasis. However, the expression and molecular mechanism of malic enzyme 3 (ME3) in GC are rarely reported. In this study, we aim to investigate the molecular mechanism of ME3 in the development of GC and to explore its potential value as a prognostic and therapeutic target in GC.METHODME3 mRNA and protein expression were evaluated in patients with GC using RT-qPCR, WB, and immunohistochemistry, as well as their correlation with clinicopathological indicators. The effect of ME3 on proliferation and metastasis was evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU) assay, transwell assay, wound healing assay, and subcutaneous injection or tail vein injection of tumor cells in mice model. The effects of ME3 knockdown on the level of metabolites and hypoxia-inducible factor-1α (HIF-1α) protein were determined in GC cells. Oxidative phosphorylation was measured to evaluate adenosine triphosphate (ATP) production.RESULTSME3 was downregulated in human GC tissues (P < 0.001). The decreased ME3 mRNA expression was associated with younger age (P = 0.02), pathological staging (P = 0.049), and lymph node metastasis (P = 0.001), while low ME3 expression was associated with tumor size (P = 0.048), tumor invasion depth (P < 0.001), lymph node metastasis (P = 0.018), TNM staging (P < 0.001), and poor prognosis (OS, P = 0.0206; PFS P = 0.0453). ME3 knockdown promoted GC cell malignancy phenotypes. Moreover, α-ketoglutarate (α-KG) and NADPH/NADP⁺ ratios were reduced while malate was increased in the ME3 knockdown group under normoxia. When cells were incubated under hypoxia, the NADPH/NADP⁺ ratio and α-KG decreased while intracellular reactive oxygen species (ROS) increased significantly. The ME3 knockdown group exhibited an increase in ATP production and while ME3 overexpression group exhibited oppositely. We discovered that ME3 and HIF-1α expression were negatively correlated in GC cells and tissues, and proposed the hypothesis: downregulation of ME3 promotes GC progression via regulating intracellular oxidative stress and HIF-1α.CONCLUSIONWe provide evidence that ME3 downregulation is associated with poor prognosis in GC patients and propose a hypothesis for the ME3 regulatory mechanism in GC progression. The present study is of great scientific significance and clinical value for exploring the prognostic and therapeutic targets of GC, evaluating and improving the clinical efficacy of patients, reducing recurrence and metastasis, and improving the prognosis and quality of life of patients.

01 Jul 2024·Cancer Science

EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2

Article

Author: Lai, Yongwei ; Xie, Bo ; Xie, Yaohong ; Zhang, Xiaohong ; Yang, Zhengyi ; Wang, Didi ; Song, Wenqi ; Zhang, Pengxia ; Han, Xu ; Xu, Yan ; Xia, Jia Qi ; Li, Wei

AbstractEnhancing sensitivity to sorafenib can significantly extend the duration of resistance to it, offering substantial benefits for treating patients with hepatocellular carcinoma (HCC). However, the role of ferroptosis in influencing sorafenib sensitivity within HCC remains pivotal. The enhancer of zeste homolog 2 (EZH2) plays a significant role in promoting malignant progression in HCC, yet the relationship between ferroptosis, sorafenib sensitivity, and EZH2 is not entirely clear. Bioinformatic analysis indicates elevated EZH2 expression in HCC, predicting an unfavorable prognosis. Overexpressing EZH2 can drive HCC cell proliferation while simultaneously reducing ferroptosis. Further analysis reveals that EZH2 amplifies the modification of H3K27 me3, thereby influencing TFR2 expression. This results in decreased RNA polymerase II binding within the TFR2 promoter region, leading to reduced TFR2 expression. Knocking down EZH2 amplifies sorafenib sensitivity in HCC cells. In sorafenib‐resistant HepG2(HepG2‐SR) cells, the expression of EZH2 is increased. Moreover, combining tazemetostat—an EZH2 inhibitor—with sorafenib demonstrates significant synergistic ferroptosis‐promoting effects in HepG2‐SR cells. In conclusion, our study illustrates how EZH2 epigenetically regulates TFR2 expression through H3K27 me3, thereby suppressing ferroptosis. The combination of the tazemetostat with sorafenib exhibits superior synergistic effects in anticancer therapy and sensitizes the HepG2‐SR cells to sorafenib, shedding new light on delaying and ameliorating sorafenib resistance.

01 Jun 2024·Metabolism

Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice

Article

Author: Mu, Wang-Jing ; Yan, Lin-Jing ; Chen, Hu-Min ; Chen, Min ; Zhu, Jie-Ying ; Li, Ruo-Ying ; Li, Yang ; Li, Xin ; Guo, Liang ; Li, Shan ; Yin, Meng-Ting ; Luo, Hong-Yang

Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10^LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10^LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.

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ME3

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