Noncanonical Functions of Telomerase and Telomerase-Targeted Cancer Therapies

Telomerase plays a key role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent researches have uncovered noncanonical properties of telomerase that are independent of its role in telomere extension. The following picture is the human telomerase structure model.

As we know, telomerase consists of TERT subunit, RNA subunit and a group of accessory protein, repaires chromosomal shrinkage resulting from the "end-replication" problem. It plays the critical role in maintaining the balance between normal cellular differentiation and the aberrant proliferation manifested in carcinogenic transformation.

Recently, researchers proposed a model of the feed-forward regulatory loop underscoring the interaction of TERT with the Wnt/?-catenin and NF-?B signaling pathways during cancer development. Reactivated TERT acts as a transcriptional modulator of Wnt/?-catenin and NF-?B signaling, resulting in the enhanced expression of Wnt and NF-?B target genes that exert cancer-promotingcompound libraries functions such as proliferation, resistance to apoptosis, and chronic inflammation. As Wnt/?-catenin and NF-?B are also transcriptional activators of TERT, the researchers suggest a feed-forward pathway (illustrated by blue arrows) that sustains Wnt/?-catenin and NF-?B–dependent transcription as well as levels of telomerase in cancer cells in a simplified schematic of signaling events.

In view of the evidence mentioned earlier linking the noncanonical functions of telomerase to cancer development and progression, targeting telomerase as an anticancer strategy seems to be an effective approach to simultaneously dampen oncogenic signaling pathways that are augmented by telomerase and disrupt the feed-forward regulatory mechanism driving chronic inflammatory/oncogenic responses and sustained telomerase activity in cancers. Furthermore, as telomerase is often upregulated in cancer cells, whereas majority of normal somatic cells have undetectable telomerase activities, telomerase-targeted cancer therapies serve to selectively eliminate tumor cells and avoid the adverse side effects. More and moreenzalutamide evidence indicates a compelling rationale for the development of therapeutic approaches that target the noncanonical roles of telomerase, instead of solely relying on conventional small-molecule inhibitors that restrict its enzymatic activity or accessibility/function at telomeres.

Previously study has been shown that,?-catenin could complex with the I?B? protein, and stabilize I?B? by inhibiting its and its association with the proteasome.

Usually, Aberrant activation of NF-?B signaling is found in triple-negative basal-like breast cancer cells, while the cause of this activation has remained elusive?The NF-?B pathway can be activated by a variety of factors. Activated NF-?B regulates kinds of target genes. Aberrant activation of NF-?B signaling is associated with various human cancers including breast cancer.

Researchers from Texas MD Anderson Cancer Center discovered that, loss of?-catenin as a mechanism by which the NF-kB pathway is activated in the basal-like subtype of breast cancer. This is highly relevant in human tumors, as alpha-catenin is specifically downregulated in human basal-like breast cancer, correlates with recurrence-free survival and negatively correlates with the activity of NF-?B signalling. Thus, Targeting the NF-?B pathway may provide therapeutic benefits to patients with basal-like, triple-negative breast cancer

Reference: alpha-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-?B signalling. Nature cell biology, 2014

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