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Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth
Synthetic lethality in DNA repair pathways is an important strategy for the selective treatment of cancer cells without harming healthy cells and developing cancer-specific drugs. The synthetic lethal interaction between the mismatch repair (MMR) protein, MutL homolog 1 (MLH1), and the mitochondrial...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165880/ https://www.ncbi.nlm.nih.gov/pubmed/35657956 http://dx.doi.org/10.1371/journal.pone.0268391 |
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author | Somuncu, Berna Ekmekcioglu, Aysegul Antmen, Fatma Merve Ertuzun, Tugce Deniz, Emre Keskin, Nazli Park, Joon Yazici, Ilgu Ece Simsek, Busra Erman, Batu Yin, Whitney Erman, Burak Muftuoglu, Meltem |
author_facet | Somuncu, Berna Ekmekcioglu, Aysegul Antmen, Fatma Merve Ertuzun, Tugce Deniz, Emre Keskin, Nazli Park, Joon Yazici, Ilgu Ece Simsek, Busra Erman, Batu Yin, Whitney Erman, Burak Muftuoglu, Meltem |
author_sort | Somuncu, Berna |
collection | PubMed |
description | Synthetic lethality in DNA repair pathways is an important strategy for the selective treatment of cancer cells without harming healthy cells and developing cancer-specific drugs. The synthetic lethal interaction between the mismatch repair (MMR) protein, MutL homolog 1 (MLH1), and the mitochondrial base excision repair protein, DNA polymerase γ (Pol γ) was used in this study for the selective treatment of MLH1 deficient cancers. Germline mutations in the MLH1 gene and aberrant MLH1 promoter methylation result in an increased risk of developing many cancers, including nonpolyposis colorectal and endometrial cancers. Because the inhibition of Pol γ in MLH1 deficient cancer cells provides the synthetic lethal selectivity, we conducted a comprehensive small molecule screening from various databases and chemical drug library molecules for novel Pol γ inhibitors that selectively kill MLH1 deficient cancer cells. We characterized these Pol γ inhibitor molecules in vitro and in vivo, and identified 3,3’-[(1,1’-Biphenyl)-4’,4’-diyl)bis(azo)]bis[4-amino-1-naphthalenesulfonic acid] (congo red; CR; Zinc 03830554) as a high-affinity binder to the Pol γ protein and potent inhibitor of the Pol γ strand displacement and one-nucleotide incorporation DNA synthesis activities in vitro and in vivo. CR reduced the cell proliferation of MLH1 deficient HCT116 human colon cancer cells and suppressed HCT116 xenograft tumor growth whereas it did not affect the MLH1 proficient cell proliferation and xenograft tumor growth. CR caused mitochondrial dysfunction and cell death by inhibiting Pol γ activity and oxidative mtDNA damage repair, increasing the production of reactive oxygen species and oxidative mtDNA damage in MLH1 deficient cells. This study suggests that the Pol γ inhibitor, CR may be further evaluated for the MLH1 deficient cancers’ therapy. |
format | Online Article Text |
id | pubmed-9165880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-91658802022-06-05 Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth Somuncu, Berna Ekmekcioglu, Aysegul Antmen, Fatma Merve Ertuzun, Tugce Deniz, Emre Keskin, Nazli Park, Joon Yazici, Ilgu Ece Simsek, Busra Erman, Batu Yin, Whitney Erman, Burak Muftuoglu, Meltem PLoS One Research Article Synthetic lethality in DNA repair pathways is an important strategy for the selective treatment of cancer cells without harming healthy cells and developing cancer-specific drugs. The synthetic lethal interaction between the mismatch repair (MMR) protein, MutL homolog 1 (MLH1), and the mitochondrial base excision repair protein, DNA polymerase γ (Pol γ) was used in this study for the selective treatment of MLH1 deficient cancers. Germline mutations in the MLH1 gene and aberrant MLH1 promoter methylation result in an increased risk of developing many cancers, including nonpolyposis colorectal and endometrial cancers. Because the inhibition of Pol γ in MLH1 deficient cancer cells provides the synthetic lethal selectivity, we conducted a comprehensive small molecule screening from various databases and chemical drug library molecules for novel Pol γ inhibitors that selectively kill MLH1 deficient cancer cells. We characterized these Pol γ inhibitor molecules in vitro and in vivo, and identified 3,3’-[(1,1’-Biphenyl)-4’,4’-diyl)bis(azo)]bis[4-amino-1-naphthalenesulfonic acid] (congo red; CR; Zinc 03830554) as a high-affinity binder to the Pol γ protein and potent inhibitor of the Pol γ strand displacement and one-nucleotide incorporation DNA synthesis activities in vitro and in vivo. CR reduced the cell proliferation of MLH1 deficient HCT116 human colon cancer cells and suppressed HCT116 xenograft tumor growth whereas it did not affect the MLH1 proficient cell proliferation and xenograft tumor growth. CR caused mitochondrial dysfunction and cell death by inhibiting Pol γ activity and oxidative mtDNA damage repair, increasing the production of reactive oxygen species and oxidative mtDNA damage in MLH1 deficient cells. This study suggests that the Pol γ inhibitor, CR may be further evaluated for the MLH1 deficient cancers’ therapy. Public Library of Science 2022-06-03 /pmc/articles/PMC9165880/ /pubmed/35657956 http://dx.doi.org/10.1371/journal.pone.0268391 Text en © 2022 Somuncu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Somuncu, Berna Ekmekcioglu, Aysegul Antmen, Fatma Merve Ertuzun, Tugce Deniz, Emre Keskin, Nazli Park, Joon Yazici, Ilgu Ece Simsek, Busra Erman, Batu Yin, Whitney Erman, Burak Muftuoglu, Meltem Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title | Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title_full | Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title_fullStr | Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title_full_unstemmed | Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title_short | Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth |
title_sort | targeting mitochondrial dna polymerase gamma for selective inhibition of mlh1 deficient colon cancer growth |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165880/ https://www.ncbi.nlm.nih.gov/pubmed/35657956 http://dx.doi.org/10.1371/journal.pone.0268391 |
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