Telomerase: from Aging to Human Cancers

Abstract

Telomeres protect DNA sequences that form the ends of chromosomes. Telomeric maintenance is a prerequisite for the indefinite proliferation of cells, cell immortalization and neoplastic growth. Telomere dysfunction also promotes chromosomal fusions that facilitate the development of human cancers. Telomerase is an active enzyme which appears in embryonic development and down-regulated in all human somatic cells prior to birth. Telomerase is transiently active in normal somatic cells throughout life and is elevated in more than 85 % of human cancers but not benign tissues. Also, expression of human telomerase reverse transcriptase (hTERT) is up-regulated in almost all human cancers but not in normal tissues. The level of telomerase activity and hTERT expression are useful diagnostic and prognostic indicator for human cancers. Progressive telomere shortening predominantly occurs during early carcinogenesis before telomerase activation. The telomere dysfunction promotes chromosomal fusions that facilitate the development of carcinomas in the p53 deficiency cells in human cancers. The activated telomerase maintains telomere length stability in almost all cancer cells. The gene encoding the endogenous telomerase inhibitor PinX1 (PIN2/TRF1), is located at human chromosome 8p23, a region frequently exhibiting heterozygosity in many common human cancers. When PinX1 binds to hTERT, it will inhibit the telomerase activity. Proteins TRF-1 and TRF-2 are negative regulators, but Tankyrase is a positive regulator of human cancers. This suggests that PinX1 could be considered as a putative tumor suppressor genes and telomerase inhibitors and considered to be used in treating cancers with highly expressed telomerase. Also, GRN163L(Imetelstat), Cisplatin, Vincristine and AZT drugs have shown potentials to decrease the telomerase activity in leukemia, lymphomas, carcinomas and sarcomas. The telomerase reactivation is vital for initiation of all human malignancies since it removes the short telomere barriers inhibitory for tumor progression. Thus, telomerase is useful biomarker for detection of cancer and aging progression. This chapter will describe the molecular characterization and regulation of telomerase activity in cancer and aging as well as its therapeutic effects.