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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

Efficient chemical inhibition of TRF1 telomere binding by compounds ETP-47228 and ETP-47037 in mouse lung adenocarcinoma-derived cellsQuantification of TRF1 levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with 10 μM ETP-47228 (24 h), and with 10 μM ETP-47037 (48 h). Representative images are shown to the right.Quantification of γH2AX levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with ETP-47228 (24 h), and with ETP-47037 (48 h). Representative images are shown to the right.Quantification of telomere-induced foci (TIFs) by double immunofluorescence with anti-RAP1 and anti-γH2AX antibodies. Representative images are shown to the right. White arrowheads: colocalization of γH2AX and RAP1.Effect of different ETP-47228 and ETP-47037 concentrations during 24 h on proliferation in lung tumor-derived cell line relative to the growth of DMSO-treated cells.Tumor growth quantification in allograft model ETP-47037 or with ETP-47228.Data information: The data represent the mean values of two to three independent experiments (A–D). Error bars represent standard errors. t-test was used to assess statistical significance.
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fig07: Efficient chemical inhibition of TRF1 telomere binding by compounds ETP-47228 and ETP-47037 in mouse lung adenocarcinoma-derived cellsQuantification of TRF1 levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with 10 μM ETP-47228 (24 h), and with 10 μM ETP-47037 (48 h). Representative images are shown to the right.Quantification of γH2AX levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with ETP-47228 (24 h), and with ETP-47037 (48 h). Representative images are shown to the right.Quantification of telomere-induced foci (TIFs) by double immunofluorescence with anti-RAP1 and anti-γH2AX antibodies. Representative images are shown to the right. White arrowheads: colocalization of γH2AX and RAP1.Effect of different ETP-47228 and ETP-47037 concentrations during 24 h on proliferation in lung tumor-derived cell line relative to the growth of DMSO-treated cells.Tumor growth quantification in allograft model ETP-47037 or with ETP-47228.Data information: The data represent the mean values of two to three independent experiments (A–D). Error bars represent standard errors. t-test was used to assess statistical significance.

Mentions: Next, we treated lung mouse adenocarcinoma cell lines with 10 μM of both ETP-47228 and ETP-47037 for 24 and 48 h and quantified TRF1 levels compared to DMSO-treated cells. Again, treatment of lung cancer cells with both ETP-47228 and ETP-47037 resulted in decreased TRF1 foci levels, increased γH2AX foci, as well as induction of TIFs (Fig7A–C). Similarly, both compounds affected proliferation from concentrations of approximately 5 μM (Fig7D).


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)

Efficient chemical inhibition of TRF1 telomere binding by compounds ETP-47228 and ETP-47037 in mouse lung adenocarcinoma-derived cellsQuantification of TRF1 levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with 10 μM ETP-47228 (24 h), and with 10 μM ETP-47037 (48 h). Representative images are shown to the right.Quantification of γH2AX levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with ETP-47228 (24 h), and with ETP-47037 (48 h). Representative images are shown to the right.Quantification of telomere-induced foci (TIFs) by double immunofluorescence with anti-RAP1 and anti-γH2AX antibodies. Representative images are shown to the right. White arrowheads: colocalization of γH2AX and RAP1.Effect of different ETP-47228 and ETP-47037 concentrations during 24 h on proliferation in lung tumor-derived cell line relative to the growth of DMSO-treated cells.Tumor growth quantification in allograft model ETP-47037 or with ETP-47228.Data information: The data represent the mean values of two to three independent experiments (A–D). Error bars represent standard errors. 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

fig07: Efficient chemical inhibition of TRF1 telomere binding by compounds ETP-47228 and ETP-47037 in mouse lung adenocarcinoma-derived cellsQuantification of TRF1 levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with 10 μM ETP-47228 (24 h), and with 10 μM ETP-47037 (48 h). Representative images are shown to the right.Quantification of γH2AX levels by immunofluorescence in lung tumor-derived cell line treated with DMSO, with ETP-47228 (24 h), and with ETP-47037 (48 h). Representative images are shown to the right.Quantification of telomere-induced foci (TIFs) by double immunofluorescence with anti-RAP1 and anti-γH2AX antibodies. Representative images are shown to the right. White arrowheads: colocalization of γH2AX and RAP1.Effect of different ETP-47228 and ETP-47037 concentrations during 24 h on proliferation in lung tumor-derived cell line relative to the growth of DMSO-treated cells.Tumor growth quantification in allograft model ETP-47037 or with ETP-47228.Data information: The data represent the mean values of two to three independent experiments (A–D). Error bars represent standard errors. t-test was used to assess statistical significance.
Mentions: Next, we treated lung mouse adenocarcinoma cell lines with 10 μM of both ETP-47228 and ETP-47037 for 24 and 48 h and quantified TRF1 levels compared to DMSO-treated cells. Again, treatment of lung cancer cells with both ETP-47228 and ETP-47037 resulted in decreased TRF1 foci levels, increased γH2AX foci, as well as induction of TIFs (Fig7A–C). Similarly, both compounds affected proliferation from concentrations of approximately 5 μM (Fig7D).

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