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Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, Mulero F, Ambrogio C, Flores JM, Megias D, Barbacid M, Pastor J, Blasco MA - EMBO Mol Med (2015)

Bottom Line: This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest.Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

No MeSH data available.


Related in: MedlinePlus

Trf1 deficiency leads to G2 arrest and mitotic defectsPercentage of Ki67-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of Ki67 immunohistochemistry (right panel).Percentage of pH3-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of pH3 immunohistochemistry (right panel). Red arrowheads: pH3-positive cells.Percentage of giant nuclei in the carcinomas of the indicated genotype.Percentage of anaphase bridges out of total anaphases in the carcinomas of the indicated genotypes.Representative images of giant nuclei, multilobulated nuclei, anaphase bridges, and multipolar mitoses. Red arrowheads indicate the corresponding mitotic aberrations indicated in the image.Data information: Error bars represent standard error. The number of mice and carcinomas analyzed per genotype is indicated. t-test was used to assess statistical significance.
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fig04: Trf1 deficiency leads to G2 arrest and mitotic defectsPercentage of Ki67-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of Ki67 immunohistochemistry (right panel).Percentage of pH3-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of pH3 immunohistochemistry (right panel). Red arrowheads: pH3-positive cells.Percentage of giant nuclei in the carcinomas of the indicated genotype.Percentage of anaphase bridges out of total anaphases in the carcinomas of the indicated genotypes.Representative images of giant nuclei, multilobulated nuclei, anaphase bridges, and multipolar mitoses. Red arrowheads indicate the corresponding mitotic aberrations indicated in the image.Data information: Error bars represent standard error. The number of mice and carcinomas analyzed per genotype is indicated. t-test was used to assess statistical significance.

Mentions: To determine whether Trf1 deletion in the context of K-RasG12V-induced lung cancer also leads to proliferation defects, we performed Ki67 immunohistochemistry directly on lung carcinoma sections. We observed a lower proliferation index (Ki67-positive cells) in Trf1Δ/ΔK-Ras+/G12Vp53−/− carcinomas compared to Trf1+/+K-Ras+/G12Vp53−/− carcinomas (Fig4A). To determine the cell cycle phase where Trf1-deleted cells showed defects, we analyzed the staining pattern of phospho-histone H3 (Ser10). A pH3 pan-nuclear staining is a distinctive feature of mitotic cells, whereas pH3 foci are characteristic of G2 cells (Hendzel et al, 1991). We found that the percentage of cells positive for G2-distinctive pH3 foci pattern was significantly increased in Trf1Δ/ΔK-Ras+/G12Vp53−/− carcinoma lesions compared to Trf1+/+K-Ras+/G12Vp53−/− lesions (Fig4B), suggestive of increased G2 arrest.


Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, Mulero F, Ambrogio C, Flores JM, Megias D, Barbacid M, Pastor J, Blasco MA - EMBO Mol Med (2015)

Trf1 deficiency leads to G2 arrest and mitotic defectsPercentage of Ki67-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of Ki67 immunohistochemistry (right panel).Percentage of pH3-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of pH3 immunohistochemistry (right panel). Red arrowheads: pH3-positive cells.Percentage of giant nuclei in the carcinomas of the indicated genotype.Percentage of anaphase bridges out of total anaphases in the carcinomas of the indicated genotypes.Representative images of giant nuclei, multilobulated nuclei, anaphase bridges, and multipolar mitoses. Red arrowheads indicate the corresponding mitotic aberrations indicated in the image.Data information: Error bars represent standard error. The number of mice and carcinomas analyzed per genotype is indicated. t-test was used to assess statistical significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520658&req=5

fig04: Trf1 deficiency leads to G2 arrest and mitotic defectsPercentage of Ki67-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of Ki67 immunohistochemistry (right panel).Percentage of pH3-positive cells in the carcinomas of the indicated genotypes (left panel). Representative images of pH3 immunohistochemistry (right panel). Red arrowheads: pH3-positive cells.Percentage of giant nuclei in the carcinomas of the indicated genotype.Percentage of anaphase bridges out of total anaphases in the carcinomas of the indicated genotypes.Representative images of giant nuclei, multilobulated nuclei, anaphase bridges, and multipolar mitoses. Red arrowheads indicate the corresponding mitotic aberrations indicated in the image.Data information: Error bars represent standard error. The number of mice and carcinomas analyzed per genotype is indicated. t-test was used to assess statistical significance.
Mentions: To determine whether Trf1 deletion in the context of K-RasG12V-induced lung cancer also leads to proliferation defects, we performed Ki67 immunohistochemistry directly on lung carcinoma sections. We observed a lower proliferation index (Ki67-positive cells) in Trf1Δ/ΔK-Ras+/G12Vp53−/− carcinomas compared to Trf1+/+K-Ras+/G12Vp53−/− carcinomas (Fig4A). To determine the cell cycle phase where Trf1-deleted cells showed defects, we analyzed the staining pattern of phospho-histone H3 (Ser10). A pH3 pan-nuclear staining is a distinctive feature of mitotic cells, whereas pH3 foci are characteristic of G2 cells (Hendzel et al, 1991). We found that the percentage of cells positive for G2-distinctive pH3 foci pattern was significantly increased in Trf1Δ/ΔK-Ras+/G12Vp53−/− carcinoma lesions compared to Trf1+/+K-Ras+/G12Vp53−/− lesions (Fig4B), suggestive of increased G2 arrest.

Bottom Line: This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest.Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

No MeSH data available.


Related in: MedlinePlus