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Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells
L type amino acid transporter 1 (LAT1) is an attractive molecular target for cancer therapy because of its overexpression in many cancer cells. JPH203, a selective LAT1 inhibitor, causes amino acid deprivation and suppresses cancer cell proliferation. However, several cancer cells showed resistance...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770514/ https://www.ncbi.nlm.nih.gov/pubmed/35046465 http://dx.doi.org/10.1038/s41598-022-04987-5 |
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author | Yamaga, Takashi Suehiro, Junichi Wada, Youichiro Sakurai, Hiroyuki |
author_facet | Yamaga, Takashi Suehiro, Junichi Wada, Youichiro Sakurai, Hiroyuki |
author_sort | Yamaga, Takashi |
collection | PubMed |
description | L type amino acid transporter 1 (LAT1) is an attractive molecular target for cancer therapy because of its overexpression in many cancer cells. JPH203, a selective LAT1 inhibitor, causes amino acid deprivation and suppresses cancer cell proliferation. However, several cancer cells showed resistance to amino acid deprivation. In this study, we aimed to elucidate the molecular mechanism of different sensitivity between 2 breast cancer cells to anti-LAT1 therapy. MDA-MB-231 cells were more resistant to growth suppression effect of JPH203 than T-47D cells (IC50 was 200 ± 12.5 μM for MDA-MB-231, and 5 ± 1.1 μM for T-47D cells; p < 0.05). Transcriptome and biochemical analysis were done in these cells in the presence/absence of JPH203. JPH203 induced intracellular amino acid deprivation stress in both cells, but it upregulated cystathionine γ lyase (CTH), an enzyme for synthesis of antioxidants, only in MDA-MB-231 cells. Moreover, siRNA-mediated CTH knockdown induced oxidative stress in response to JPH203 leading to decreased cell viability in MDA-MB-231 cells. These results suggest that activation of anti-oxidation pathways in response to amino acid deprivation confers resistance to anti-LAT1 therapy. |
format | Online Article Text |
id | pubmed-8770514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87705142022-01-20 Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells Yamaga, Takashi Suehiro, Junichi Wada, Youichiro Sakurai, Hiroyuki Sci Rep Article L type amino acid transporter 1 (LAT1) is an attractive molecular target for cancer therapy because of its overexpression in many cancer cells. JPH203, a selective LAT1 inhibitor, causes amino acid deprivation and suppresses cancer cell proliferation. However, several cancer cells showed resistance to amino acid deprivation. In this study, we aimed to elucidate the molecular mechanism of different sensitivity between 2 breast cancer cells to anti-LAT1 therapy. MDA-MB-231 cells were more resistant to growth suppression effect of JPH203 than T-47D cells (IC50 was 200 ± 12.5 μM for MDA-MB-231, and 5 ± 1.1 μM for T-47D cells; p < 0.05). Transcriptome and biochemical analysis were done in these cells in the presence/absence of JPH203. JPH203 induced intracellular amino acid deprivation stress in both cells, but it upregulated cystathionine γ lyase (CTH), an enzyme for synthesis of antioxidants, only in MDA-MB-231 cells. Moreover, siRNA-mediated CTH knockdown induced oxidative stress in response to JPH203 leading to decreased cell viability in MDA-MB-231 cells. These results suggest that activation of anti-oxidation pathways in response to amino acid deprivation confers resistance to anti-LAT1 therapy. Nature Publishing Group UK 2022-01-19 /pmc/articles/PMC8770514/ /pubmed/35046465 http://dx.doi.org/10.1038/s41598-022-04987-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yamaga, Takashi Suehiro, Junichi Wada, Youichiro Sakurai, Hiroyuki Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title | Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title_full | Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title_fullStr | Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title_full_unstemmed | Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title_short | Induction of CTH expression in response to amino acid starvation confers resistance to anti-LAT1 therapy in MDA-MB-231 cells |
title_sort | induction of cth expression in response to amino acid starvation confers resistance to anti-lat1 therapy in mda-mb-231 cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770514/ https://www.ncbi.nlm.nih.gov/pubmed/35046465 http://dx.doi.org/10.1038/s41598-022-04987-5 |
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