‘Mitotic spindles’ could help develop better chemo drugs

A good yarn: chromosomes are shared out to dividing cells by mitotic spindles. Triesquid

Cells use a tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process goes wrong it can lead to cancer.

For many years we’ve been interested in how the spindle divides up genetic material accurately. When a cell divides it must make sure that each daughter cell receives just one copy of each chromosome, which carries DNA to the new cell. Defects in this process can lead to cells having the wrong amount of chromosomes, which can lead to cancer or birth defects.

Anti-cancer drugs have been developed which target the mitotic spindle and destroy dividing cells in tumours. But these drugs have significant side effects. In my lab, we’re trying to understand how the mitotic spindles work in order to develop drugs that are more targeted and have fewer side effects.

Mitotic spindle: chromosomes in blue, microtubles in green. Wikimedia Commons/Afunguy

Chromosomes are allocated by the mitotic spindle, which is made up of many thin filaments called microtubules. These are held together in bundles and these bundles share the chromosomes equally during mitosis.

Colleagues and I at Warwick Medical School have shown in a paper published in The Journal of Cell Biology that a team of three proteins - called the TACC3–ch-TOG–clathrin complex - work to hold the spindle’s microtubules together and stabilise the bundle through a system of “bridges”. Drugs such as Taxol (Paclitaxel) have been used very effectively in chemotherapy because they poison microtubles and inhibit the mitotic spindle. This stops cancer cells from dividing and causes them to die.

However, the disadvantage is that microtubules are needed for many functions in non-cancerous cells. This means that existing treatments don’t discriminate between cancerous and normal cells. So the use of Taxol and others in its family, for example, cause side effects such as nerve damage. If we could target the mitotic spindle proteins, rather than microtubules, we may be able to develop effective anti-cancer drugs with far fewer side effects.

We’ve found that in cancer cells, the amount of the protein complex is either too low or too high. This suggests that these proteins could be targeted for potential anti-cancer therapies in the future.

Our research group, together with Richard Bayliss’ lab at the University of Leicester, have recently described how the proteins in the TACC3–ch-TOG–clathrin complex bind to one another. In turn this led us to understand how the complex binds to microtubules. By taking out the TACC3 protein, the clathrin loses its function and is no longer able to create some of the bridges that bind the microtubles.

It’s important as we can use this information to think of ways to break the complex apart or to prevent it binding microtubules. From this, we may be able to disrupt the function of the protein complex in dividing cells and inhibit the sharing of chromosomes during mitosis, causing the death of cancerous cells.

The research is in the early stages, but we have also discovered that an enzyme called Aurora A kinase controls the assembly of the protein complex. Aurora A is often amplified in tumours and clinical trials into inhibiting its role are already underway into drugs that cause the TACC3-ch-TOG-clathrin complex to fall apart and actually break away from the mitotic spindle altogether.

When treating cancer we still often cause damage in other areas. Understanding and controlling the action of the mitotic spindle could help us to better target treatment by directly shutting down defective cells.