Telomere dysfunction and telomerase activation in cancer – a pathological paradox?

Abstract

Telomerase is expressed in more than 90% of human cancers. Telomere maintenance by this enzyme is believed to safeguard genomic integrity in neoplastic cells. Nevertheless, many telomerase-expressing tumours exhibit chromosomal instability triggered by short, dysfunctional telomeres, implying that active telomerase is not sufficient for preserving a functional telosomic nucleoprotein complex in cancer cells. We here examine three possible solutions to this ostensible paradox. First, prior to telomerase activation, telomere erosion may have evolved to a level where telomeric repeat sequences are too short to provide a functional substrate for telomerase enzyme activity. Second, mechanisms other than the continuous telomere erosion counteracted by telomerase may contribute to rapid shortening of telomere repeats. Third, dysfunction of telomere-regulating proteins may result in direct telomere uncapping. Moreover, telomerase may contribute to tumour development also through mechanisms unrelated to telomere length maintenance. Taken together, the available data on the role of telomerase in cancer strongly support that inhibition of this enzyme is a feasible strategy for cancer therapy.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response

“…The reasons for this are unknown, but telomerase activity and telomere length change along very different time lines and under different circumstances, and thus may be unrelated. 40,58 Other reasons for the lack of significant correlations between telomere length and telomerase activity have been proposed, 68 including the shuttling of telomerase from the nucleus to the mitochondria under conditions of oxidative stress, 69,70 and the possibility that telomerase may decrease the number of PBMC’s with ‘short’ telomeres without significantly altering average PBMC telomere length. 61 It is possible that depression-related inflammation and/or oxidative stress contributed to our findings, as these may be associated both with shortened telomeres 7,15,71 and with stimulatory effects on telomerase activity 52–56 (although see ref.…”

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

“…However there is a complete lack of detailed structural information about this ideal anticancer target. The different mechanisms of action of telomerase and its role in cancer chemotherapy have been recently reviewed by Calcagnile and Gisselsson [40]. Flavonoids have been considered in recent years as promising ligands for their use in cancer prevention and therapy [39].…”

“…GSK-3 is an attractive target for various diseases including Alzheimer's, bipolar disorder, diabetes, cancer and malaria. Even though the and isoforms are 97% identical with respect to their kinase domain, studies performed by Phiel et al [48] showed that selective reduction of and form leads to a decrease and increase in A 40 and A 42 (the primary constituents of the amyloid plaques in Alzheimer's disease), respectively. We previously investigated 4-arylmaleimide derivatives from Smith et al (VI) [49].…”

Leukocyte telomere length, breast cancer risk in the offspring: The relations with father's age at birth

“…This activation does not elongate telomeres; rather it prevents further telomere shortening. Thus, most cancers display short telomeres and robust telomerase activity (Calcagnile and Gisselsson, 2007; Kim et al, 1994). …”