Tankyrase protein plays an important role in helping drive bowel cancer

The inner workings of the main protein involved in an extensive range of cellular processes have been disclosed by researchers. This possibly sets the stage for improved and less toxic cancer drugs.

Tankyrase protein plays an important role in helping drive bowel cancer
Using cryo-electron microscopy, researchers obtained a detailed map (shown in orange) of the chain-like tankyrase structure. By interpreting this map and reconstructing the tankyrase molecules amino acid by amino acid (red), they deciphered how tankyrase is activated by “self-assembling”. Image Credit: Sebastian Guettler, ICR.

With the availability of Nobel Prize-winning microscopy methods, the scientists disclosed how the tankyrase protein turns on and off by itself through self-assembling into 3D chain-like structures.

Their study, reported in the journal Nature, discloses vital structural knowledge into the elusive but essential tankyrase protein. This plays an especially significant role in aiding to drive bowel cancer.

Less toxic drugs

At The Institute of Cancer Research, London, researchers believe their study will set the stage for new types of cancer treatment that exhibits the potential to regulate tankyrase in a more accurate manner compared to what is possible at present, with some side effects.

The basic breakthrough could have effects for treating several cancers, as well as diabetes and inflammatory, cardiac, and neurodegenerative diseases.

The study was primarily funded by Cancer Research UK, Wellcome, and The Institute of Cancer Research (ICR), which is itself serving as a charity as well as a research institute. Also, it was assisted by the Lister Institute of Preventive Medicine.

Signals fuelling bowel cancer

Tankyrase is an essential protein that helps so-called “Wnt signaling”—signals that are necessary for the body to retain stem cells and perform processes like cell division and development.

However, when left uncontrolled, it can fuel bowel cancer, among others. Also, tankyrase regulates other cell functions that are vital to cancer, like the maintenance of the ends of chromosomes and the telomeres.

Dissimilar to the PARP1 protein from the same “PARP family,” tankyrase is yet to be well understood. While drugs that are blocking PARP1 have already made it to the clinic, researchers still do not completely understand how tankyrase has been made to turn on, how it functions, or how to block it without resulting in undesired side effects.

Initially, in this study performed, researchers draw parallels between the activation mechanism of tankyrase and PARP1. They recommend that, in the same way as PARP1, tankyrase functions by being recruited to a particular site and “self-assembling,” clustering and altering its 3D structure to trigger itself and execute its function.

Existing drugs never reached human trials

In the past 10 years, researchers have come up with drugs to block tankyrase in an attempt to treat bowel cancer. However, because Wnt signaling has been involved in an extensive range of processes, the drugs result in too many side effects for them to attain clinical trials.

To actually comprehend how tankyrase inhibitors tend to and how to develop fewer toxic treatments, researchers at the ICR set forth to find new structural information with the help of cutting-edge cryo-electron microscopy. This extremely strong type of microscopy freezes samples at –180 °C to allow minute details of protein shape to be imaged.

The method enabled them to envision and capture how tankyrase tends to “self-assembles” into fibers–chain-like structures–and why fiber formation is required for tankyrase to trigger itself.

Designing “structurally different” drugs

Scientists believe the “domains”—particular regions of the protein linked to various functions enable tankyrase to assemble and disassemble into various structures that are known to be exciting targets for cancer drugs in the future.

Also, they believe that, based on which structural domains drugs bind to, not all tankyrase inhibitors will affect Wnt signaling in a similar way.

The belief is that scientists will be able to design structurally various tankyrase inhibitors—ones that are secure and affordable. This is immediately required for treating bowel cancer and other diseases with which tankyrase has been connected.

“We’re playing catch up”

Our study has provided vital new information about a particular protein molecule called tankyrase, which plays an important role in bowel cancer and other diseases but has so far eluded our understanding. We’re playing catch up—we have all these drugs to block tankyrase being created, but we don’t have enough basic understanding to use them as treatments.”

Professor Sebastian Guettler, Study Leader and Head, Division of Structural Biology, The Institute of Cancer Research

Guettler added, “We have shown how tankyrase is switched on and can go from a ‘lazy’ enzyme to an active one. If we can create better, less toxic drugs to control this process, we could pave the way for an effective bowel cancer treatment in the future.”

This study could have wide implications.

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:

These fundamental findings help us understand how the extremely important tankyrase protein works within cells. Almost all bowel cancers have hyperactive Wnt-signalling that operates through tankyrase, and they could therefore potentially be treated with drugs targeting it.

I am hopeful these key advances in our understanding of tankyrase will help us overcome the limitations of currently available drug candidates—hopefully bringing us a step closer to a new targeted bowel cancer treatment. Tankyrase is also responsible for regulating a wide range of processes relevant to a variety of diseases, not just cancer, so this research could hav broad implications.”

Paving the way for new treatments in the future

PARPs can help cancer cells fix their damaged DNA, so they’re crucial targets for cancer-killing drugs. We’re proud to have supported this research that builds knowledge of the less studied tankyrase PARPs and could help pave the way for new treatments in the future.”

Dr Marianne Baker, Research Information Manager, Cancer Research

Baker continued, “This paper is an example of important discovery research that deepens our understanding of biology, which is vital for designing new cancer drugs.”

It also builds on Cancer Research UK’s successful history with PARP inhibitors. In the 1990s, Cancer Research UK-funded scientists at the ICR played a key role in developing drugs that inhibit PARP proteins and stop cancer cells repairing themselves. Tens of thousands of people across the world now receive these treatments,” added Baker.

Source:
Journal reference:

Pillay, N., et al. (2022) Structural basis of tankyrase activation by polymerization. Nature. doi.org/10.1038/s41586-022-05449-8

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
Post a new comment
Post
You might also like...
Novel approach increases the protein production efficiency of synthetic mRNAs