Inhibition of Telomerase Recruitment and Cancer Cell Death

Background: A specific surface of the TPP1 protein, called the TEL patch, mediates telomerase recruitment in human cells. Results: TEL patch deficiency caused cancer cell death, which was exacerbated by inhibition of telomerase enzymatic activity. Conclusion: TEL patch mutations are detrimental to cancer cell viability. Significance: This work encourages the development of new combinational cancer therapies that involve simultaneous inhibition of telomerase recruitment and telomerase activity. Continued proliferation of human cells requires maintenance of telomere length, usually accomplished by telomerase. Telomerase is recruited to chromosome ends by interaction with a patch of amino acids (the TEL patch, for TPP1 glutamate (E) and leucine (L)-rich patch) on the surface of telomere protein TPP1. In previous studies, interruption of this interaction by mutation prevented telomere extension in HeLa cells, but the cell culture continued to grow. We now show that the telomerase inhibitor BIBR1532 acts together with TEL patch mutations to inhibit the growth of HeLa cell lines and that apoptosis is a prominent mechanism of death of these cells. Survivor cells take over the population beginning around 40 days in culture. These cells no longer express the TEL patch mutant TPP1, apparently because of silencing of the expression cassette, a survival mechanism that would not be available to cancer cells. These results provide hope that inhibiting the binding of telomerase to the TEL patch of TPP1, perhaps together with a modest inhibition of the telomerase enzyme, could comprise an effective anticancer therapy for the approximate to 90% of human tumors that are telomerase-positive.