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MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation

Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used for effective me...

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Autores principales: Bondarev, Nikolay, Ivanenko, Karina, Khabusheva, Elmira, Lebedev, Timofey, Manukhov, Ilya, Prassolov, Vladimir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657631/
https://www.ncbi.nlm.nih.gov/pubmed/36361596
http://dx.doi.org/10.3390/ijms232112807
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author Bondarev, Nikolay
Ivanenko, Karina
Khabusheva, Elmira
Lebedev, Timofey
Manukhov, Ilya
Prassolov, Vladimir
author_facet Bondarev, Nikolay
Ivanenko, Karina
Khabusheva, Elmira
Lebedev, Timofey
Manukhov, Ilya
Prassolov, Vladimir
author_sort Bondarev, Nikolay
collection PubMed
description Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used for effective methionine depletion. In this work, we show that MGL S3, a genetically engineered protein comprised of MGL from Clostridium sporogenesis fused to epidermal growth factor (EGF)-like peptide, reduces, in vitro, the number of cancer cells of four different origins—neuroblastoma, lung, breast, and colon cancer. We reveal that MGL S3 is more toxic for neuroblastoma SH-SY5Y and lung cancer H1299 cells compared to MGL tetani, and causes cell death by the induction of apoptosis. In addition, the observed death of cells treated with MGL S3 is accompanied by the prominent downregulation of ERK activity. By the analysis of transcriptomic data of more than 1500 cancer cell lines and patient samples, we show that the high expression of four genes from the methionine metabolism pathway (AHCY, CBS, DNMT3A, and MTAP) is associated with poor prognosis for breast cancer and neuroblastoma patients. Additionally, cells of these origins are characterized by a high correlation between EGFR dependency and DNMT3A/CBS expression. Finally, we demonstrate the ability of MGL S3 to enhance the sensitivity of H1299 cells to EGFR inhibition with gefitinib.
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spelling pubmed-96576312022-11-15 MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation Bondarev, Nikolay Ivanenko, Karina Khabusheva, Elmira Lebedev, Timofey Manukhov, Ilya Prassolov, Vladimir Int J Mol Sci Article Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used for effective methionine depletion. In this work, we show that MGL S3, a genetically engineered protein comprised of MGL from Clostridium sporogenesis fused to epidermal growth factor (EGF)-like peptide, reduces, in vitro, the number of cancer cells of four different origins—neuroblastoma, lung, breast, and colon cancer. We reveal that MGL S3 is more toxic for neuroblastoma SH-SY5Y and lung cancer H1299 cells compared to MGL tetani, and causes cell death by the induction of apoptosis. In addition, the observed death of cells treated with MGL S3 is accompanied by the prominent downregulation of ERK activity. By the analysis of transcriptomic data of more than 1500 cancer cell lines and patient samples, we show that the high expression of four genes from the methionine metabolism pathway (AHCY, CBS, DNMT3A, and MTAP) is associated with poor prognosis for breast cancer and neuroblastoma patients. Additionally, cells of these origins are characterized by a high correlation between EGFR dependency and DNMT3A/CBS expression. Finally, we demonstrate the ability of MGL S3 to enhance the sensitivity of H1299 cells to EGFR inhibition with gefitinib. MDPI 2022-10-24 /pmc/articles/PMC9657631/ /pubmed/36361596 http://dx.doi.org/10.3390/ijms232112807 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bondarev, Nikolay
Ivanenko, Karina
Khabusheva, Elmira
Lebedev, Timofey
Manukhov, Ilya
Prassolov, Vladimir
MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title_full MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title_fullStr MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title_full_unstemmed MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title_short MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
title_sort mgl s3 chimeric enzyme drives apoptotic death of egfr-dependent cancer cells through erk downregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657631/
https://www.ncbi.nlm.nih.gov/pubmed/36361596
http://dx.doi.org/10.3390/ijms232112807
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