Targeting Shelterin via TRF1 to Degrade Telomeres in Cancer Cells

Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.

In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.

A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.



Back in the seventies, the cancer slogan was(we plan to have cancer cured in your lifetime) Later, the slogan was to have a cure by 2015. So far, they failed. Now they're hoping to point of treating as a chronic disease, treatable but not curable. Disappointing:(

Posted by: Robert Church at July 15th, 2019 11:41 AM

@Robert Church
Now we have better understanding of the complexity of cancer. And cancer is not a single disease. Rather 70 if not 100. Some cancers are easily cured, or rather put in "remission", some can have only palliative treatments. The researchers have become more humble over the years.

Curing all cancers, including the rarest ones might take longer than stopping aging. Until we have working (reliably) immune therapies we agree basically in the day ages of the cancer fight

Posted by: Cuberat at July 15th, 2019 12:56 PM

The genomics approach has failed for obvious reasons - once cancer gets going, it maintains short telomeres to allow for very fast mutation rates, so immunotherapy targetting a particular cancer genotype will likely fail. There's nothing wrong with trying to find more ubiquitous targets, like telomerase - but I have the feeling the solution will have more to do with mitochondria.

If we solve aging, cancer rates will be reduced back down to what they are for young people. Solving the non-aging related cancers, and curing the ones that do crop up, even in the young, is another problem, but in my view, not as urgent as solving aging.

Posted by: Mark at July 16th, 2019 4:29 AM

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