Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway

Zhou, Feng; Yuan, Ziyi; Gong, Yuyan; Li, Luyao; Wang, Yanmao; Wang, Xian; Ma, Chunbo; Yang, Lehe; Liu, Zhiguo; Wang, Liangxing; Zhao, Haiyang; Zhao, Chengguang; Huang, Xiaoying

doi:10.1016/j.biopha.2023.114412

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…In this investigation, our attention was directed towards the MTHFD2 enzyme, which was studied in conjunction with a potent isoenzyme inhibitor, DS44960156 [56]. MTHFD2 was chosen for its prevalent role in several cancer cell lines and the significant implications of its inhibition on cellular growth and survival [57][58][59][60]. We obtained the crystallographic data of MTHFD2 in a complex with DS44960156 (PDB ID: 6JIB) from the Protein Data Bank (PDB) [61] with the from 15 December 2023.…”

Section: Molecular Docking Preparationmentioning

confidence: 99%

Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors

Binmujlli

2024

Pharmaceutics

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In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([125I]anastrozole) and radioiodinated epirubicin ([125I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [125I]anastrozole and [125I]epirubicin with MTHFD2. Molecular docking illustrates that [125I]epirubicin has a superior binding free energy (∆Gbind) of −41.25 kJ/mol compared to −39.07 kJ/mol for [125I]anastrozole and −38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme–ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [125I]anastrozole and [125I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[125I]anastrozole and 16.84 Å for MTHFD2-[125I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [125I]anastrozole and [125I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of −48.49 ± 0.11 kJ/mol for [125I]anastrozole and −43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [125I]anastrozole and [125I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [125I]anastrozole and [125I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results.

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Section: Molecular Docking Preparationmentioning

confidence: 99%

Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors

Binmujlli

2024

Pharmaceutics

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“…This study focused on the enzyme target MTHFD2 in complex with a potent isoenzyme inhibitor (DS44960156) (PDB ID: 6JIB) [44], which was chosen due to its presence in various cancer cell lines and potential impact on cell proliferation and viability [22,24,25,27]. The crystal structure of the enzyme-inhibitor complex (PDB ID: 6JIB) was obtained from the Protein Data Bank in PDB [45] format on 5 October 2023.…”

Section: Molecular Docking and Admet Prediction 251 Protein Structure...mentioning

confidence: 99%

“…Further investigation into the molecular mechanisms underlying these effects is needed, particularly using molecular docking techniques to probe interactions between the compounds and the MTHFD2 enzyme. The MTHFD2 enzyme is crucial in cancer cell metabolism and could provide insights into the underlying mechanisms of these anticancer effects, allowing for a more comprehensive understanding of its therapeutic potential [22][23][24][25][26][27].…”

Section: Gc-ms and Hplc Analyses Of The Extractmentioning

confidence: 99%

“…Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is an enzyme that has recently come to the forefront due to its high expression in various cancer types, including non-small cell lung cancer, breast cancer, prostate cancer, and blood cancer [22][23][24][25][26][27]. This enzyme plays a pivotal role in mitochondrial folate one-carbon metabolism and is also referred to as NMDMC (NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenasecyclohydrolase) [28].…”

Section: Introductionmentioning

confidence: 99%

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Identification and Absorption–Distribution–Metabolism–Excretion–Toxicity Prediction of Potential MTHFD2 Enzyme Inhibitors from Urtica dioica Ethanolic Leaf Extract

Alshammari

2024

Processes

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This study aimed to explore the potential of Urtica dioica (U. dioica) ethanolic leaf extract for cancer treatment by identifying its components, evaluating its effects on cancer cell lines, and analyzing its molecular docking. The objective of this study was to investigate the anticancer properties of U. dioica ethanolic leaf extract and assess its potential as a therapeutic strategy for cancer treatment. This study utilized high-performance liquid chromatography (HPLC) to analyze the chemical composition of U. dioica ethanolic leaf extract. The anticancer effects of the extract were evaluated by assessing cell viability, determining IC50 values, and conducting ADMET analysis after oral administration. U. dioica ethanolic leaf extract was found to contain methyl hexadecanoate as its primary component, along with flavonoids and polyphenols. It effectively reduced cell viability in various tested cancer cell lines, with IC50 values varying for each cell line. The duration of treatment significantly influenced cell viability, with the most significant reduction observed after 48 h. Molecular docking studies suggested that catechin, kaempferol, and quercetin-3-O-rutinoside may have potential as inhibitors of the MTHFD2 enzyme. This study revealed the potential of U. dioica and its compounds in cancer treatment. Ethanolic leaf extract has been shown to have anticancer effects on various cancer cell lines, with catechin and kaempferol showing promise as inhibitors of the MTHFD2 enzyme. Further research is warranted to explore the therapeutic implications of U. dioica in cancer treatment.

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“…Elevated MTHFD2 levels have been associated with unfavorable results in head and neck squamous cell carcinoma (HNSC), as well as in breast cancer, lung adenocarcinoma (LUAD), and ovarian cancer (OC) [10,[12][13][14][15]. Moreover, the abnormal expression of MTHFD2 is implicated in cancer proliferation and metastasis [16,17], while the knockdown or drug intervention of MTHFD2 in cancer cell lines impaired tumor growth in non-small cell lung cancer, acute myeloid leukemia (AML), colorectal cancer and nasopharyngeal carcinoma [18][19][20][21]. In addition, some studies evaluated the function of MTHFD2 within the tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

Identification of MTHFD2 as a Prognostic Factor and Evaluation of its Role in Macrophage Polarization in Kidney Renal Clear Cell Carcinoma by Pan-Cancer Analysis

Zhou,

Zheng,

et al. 2024

Preprint

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The enzyme methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in the mitochondrial folate cycle plays oncogenic roles in different types of cancers; nonetheless, the function of MTHFD2 in tumor immunity and underlying mechanisms are unclear. A systematic bioinformatics analysis and lab experiments were conducted to explore the role in the tumor microenvironment (TME). Elevated levels of MTHFD2 expression were observed in most cancer types, correlating with a poor clinical prognosis. MTHFD2 was found to influence immune cell infiltration within the TME in diverse cancer types. Single-cell RNA sequencing data from the TISCH database revealed predominant expression of MTHFD2 in macrophages within KIRC tissues. Immunohistochemical staining analysis confirmed the upregulation of MTHFD2 in KIRC tissues, indicating an unfavorable clinical outcome. Multiplex immunohistochemistry staining demonstrated the concurrent presence of CD163 and CD68 in KIRC tissues exhibiting elevated levels of MTHFD2 expression. Co-culture experiments showed that inhibition of MTHFD2 reversed macrophage polarization induced by tumor-associated macrophages in 786-O renal cell carcinoma (RCC) cells. Furthermore, MTHFD2 inhibition induced G2/M phase arrest in RCC cells. MTHFD2 serves as a prognostic factor and exerts significant influence on shaping an immunosuppressive microenvironment in different types of malignancies, particularly by influencing macrophage infiltration and polarization in KIRC tissues.

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Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway

Cited by 7 publications

References 41 publications

Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors

Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors

Identification and Absorption–Distribution–Metabolism–Excretion–Toxicity Prediction of Potential MTHFD2 Enzyme Inhibitors from Urtica dioica Ethanolic Leaf Extract

Identification of MTHFD2 as a Prognostic Factor and Evaluation of its Role in Macrophage Polarization in Kidney Renal Clear Cell Carcinoma by Pan-Cancer Analysis

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