ArticleOncotarget2015
A small-molecule inhibitor suppresses the tumor-associated mitochondrial NAD(P)+-dependent malic enzyme (ME2) and induces cellular senescence.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- A cryptic allosteric pocket shapes isoform-selective inhibition of human malic enzymes.Protein science : a publication of the Protein Society · 2026Article
- Harnessing glucose metabolism with nanomedicine for cancer treatment.Theranostics · 2024Review
- Targeting human mitochondrial NAD(P)Cellular oncology (Dordrecht, Netherlands) · 2023Article
- Suppression of the human malic enzyme 2 modifies energy metabolism and inhibits cellular respiration.Communications biology · 2023Article
- In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma.ACS medicinal chemistry letters · 2023Article
- Integrative structural and functional analysis of human malic enzyme 3: A potential therapeutic target for pancreatic cancer.Heliyon · 2022Article
- Discovery and Characterization of a Novel Allosteric Small-Molecule Inhibitor of NADPBiochemistry · 2022Article
- The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease.International journal of molecular sciences · 2022Review
- Malic enzyme 2 promotes the progression of hepatocellular carcinoma via increasing triglyceride production.Cancer medicine · 2021Article
- Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2021Article
- Article
- Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors.Cell systems · 2021Article
- Structural and Molecular Dynamics ofACS infectious diseases · 2021Article
- NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2020Review
- Overexpression of Malic Enzyme 2 Indicates Pathological and Clinical Significance in Oral Squamous Cell Carcinoma.International journal of medical sciences · 2020Article
- Functional Roles of Metabolic Intermediates in Regulating the Human Mitochondrial NAD(P)Scientific reports · 2019Article
- Inhibition of malic enzyme 1 disrupts cellular metabolism and leads to vulnerability in cancer cells in glucose-restricted conditions.Oncogenesis · 2017Article
- Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells.Frontiers in oncology · 2017Review
- Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here, we found a natural compound, embonic acid (EA), that can specifically inhibit the enzymatic activity of mitochondrial NAD(P)+-dependent malic enzyme (m-NAD(P)-ME, ME2) either in vitro or in vivo. The in vitro IC50 value of EA for m-NAD(P)-ME was 1.4 ± 0.4 μM. Mutagenesis and binding studies revealed that the putative binding site of EA on m-NAD(P)-ME is located at the fumarate binding site or at the dimer interface near the site. Inhibition studies reveal that EA displayed a non-competitive inhibition pattern, which demonstrated that the binding site of EA was distinct from the active site of the enzyme. Therefore, EA is thought to be an allosteric inhibitor of m-NAD(P)-ME. Both EA treatment and knockdown of m-NAD(P)-ME by shRNA inhibited the growth of H1299 cancer cells. The protein expression and mRNA synthesis of m-NAD(P)-ME in H1299 cells were not influenced by EA, suggesting that the EA-inhibited H1299 cell growth occurs through the suppression of in vivo m-NAD(P)-ME activity EA treatment further induced the cellular senescence of H1299 cells. However, down-regulation of the enzyme-induced cellular senescence was not through p53. Therefore, the EA-evoked senescence of H1299 cells may occur directly through the inhibition of ME2 or a p53-independent pathway.
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