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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
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.
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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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