Abstract #3471: Telomere dysfunction reinforces therapy-induced cellular senescence Free

Accelerated cellular senescence (ACS) is an emerging concept implicating sustained telomere-independent cell cycle arrest of immortalized cells in response to antineoplastic drugs, ionizing radiation, differentiating agents, oxidative stress or the presence of selective oncogenic stimuli. We have previously demonstrated in epithelial tumor cell lines exposed to chemotherapeutic agents, that prolonged cell cycle arrest is a reversible event for small subsets of cells able to bypass senescence and reenter the cell cycle leading to tumor progression. It has been recognized that senescent cells in irreversible cell-cycle arrest characteristically demonstrate massive loss of telomere length. We have found among tumor cells able to escape chemotherapy-induced senescence, either partial or total recovery of their telomere loss. Early treated \#8220;reversible\#8221; senescent cells maintain expression of telomerase activity, whereas \#8220;irreversible\#8221; senescent cells in cell-cycle arrest express minimal telomerase activity. Uncapping events occur at the telomere ends in response to DNA damage, including the dissociation of TRF2 and POT1 proteins from the telomere ends followed by rapid degradation of telomere length. Using an adenoviral approach, we have prevented recapping at the uncapped telomere ends by expressing the dominant negative TRF2^{\#916;B\#916;M} allele in senescent tumor cells. The selective expression of this mutant protein significantly reduced escape colony formation when compared to the wild-type or defective TRF2 allele. Additionally, the application of pharmacological telomerase inhibitors TMPyP4 and TAG-6 also reduced senescence reversal. Altogether these results suggest that uncapping and loss of telomere length in response to DNA damage plays an important role in preventing escape from therapy-induced senescence, and regulation of telomere capping events following chemotherapy may represent a novel approach to cancer treatment.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3471.