Telomere maintenance, by telomerase and/or homologous recombination (HR), plays a key role in providing unlimited growth potential to cancer cells. We have shown that telomerase activity is markedly elevated and telomeres are shorter in Barrett's adenocarcinoma cells relative to normal cells, and inhibitors of telomerase cause suppression of cancer cell growth in vitro and in xenograft model of human BEAC in SCID mice. The mechanisms of telomere maintenance and their activation during carcinogenesis are not known. However we have found that HR activity and recombinase expression are markedly elevated and ALT associated PML bodies are highly expressed in BEAC cells, providing an evidence of HR based telomere elongation in BEAC. Moreover elevated HR causes genomic rearrangements and may also lead to activation of oncogenes, including the induction of telomerase. We have also shown that key HR proteins, including recombinase, physically interact with telomerase in BEAC cells and suppression of these proteins suppresses telomerase activity and induces apoptosis. These observations indicate that elevated HR in BEAC may be involved in both the telomerase regulation and telomerase-independent maintenance of telomeres. Concomitant suppression of both telomerase and HR may enhance telomere shortening and apoptosis in BEAC by acting at multiple levels.
The specific aims of this proposal are: 1) To study telomere function and expression of related genes in well defined human tissues in different histological stages of BEAC. Defined abnormal cells will be obtained using laser capture microscopy. 2) To determine the roles of HR in telomere function and cell survival in BEAC cultures by transgenic suppression or upregulation of HR genes. The influence of these manipulations on telomerase activity, telomere length, and cell survival will be determined. 3) To examine the therapeutic potential of telomerase and HR inhibitors alone and in combination on additional BEAC cell lines in vitro and in a xenograft model of human BEAC in SCID mice. Relevance to Public Health: In this proposal we will study the mechanisms by which esophageal cancer cells prevent shortening of their chromosomes ends and hence attain unlimited growth potential. We will also identify the agents which would re-activate shortening of chromosome ends in these cells and inhibit the growth of this cancer.
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