Abstract
Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-RasG12V-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. 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.
Highlights
Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth
To assess the effect of Trf1 abrogation in the context of lung cancer induced by expression of the K-RasG12V oncogene, we crossed K-Ras+/LSLG12Vgeo mice (Guerra et al, 2003) to a strain carrying a floxable allele of Trf1 (Trf1lox/lox) either wild-type or deficient for p53 (p53À/À) (Martinez et al, 2009) (Fig. 1A)
Aberrant telomerase activation is a common feature of human cancers, where it allows the growth of malignant cells by ensuring maintenance of a minimal functional telomere length that permits cell division (Kim et al, 1994; Hahn et al, 1999; Gonzalez-Suarez et al, 2000)
Summary
Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. We address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf ablation impairs the growth of p53-null K-RasG12V-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer
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