Every time a cell divides, its chromosomes go through a country dance. Forming pairs, they line up in a neat row, facing each other, before dramatically shimmying to opposite ends of the room along long ‘spindles’ of protein.
Having split its dancing partners, the cell pinches itself in two and separates them forevermore. The spindle is a crucial part of this dance: without it, the chromosomes never separate and the cell can’t divide.
To try to exploit this, some cancer drugs such as taxanes work by interfering with cancer cells’ spindles, stopping them from dividing. But over time, tumor cells can adapt to become resistant to these drugs.
This can be particularly frustrating in treating ovarian cancers. Often patients fare extremely well after their first round of chemo, only to find their cancer starts growing again. This makes the disease particularly difficult to treat, as patients often need many rounds of chemotherapy.
Recognizing this, an international research group led by one of our scientists, Dr. Ahmed Ahmed, who has recently moved from the University of Cambridge to Oxford University, and Dr. Robert Bast, from the University of Texas M.D. Anderson Cancer Center, has been trying to crack this problem by hunting down the genes responsible for this resistance, with the ultimate aim of developing new drugs to overcome the problem.
Their latest, somewhat surprising discovery was revealed this week. The team has found a new player in ovarian cancer drug resistance – a gene previously only known to be involved in helping fat and liver cells recover from starvation. It now turns out this gene also plays a key role in helping the spindle form during cell division, and thus helping cancer’s genetic dancers do their dance.
A surprising result
To make their discovery, the researchers used a technique called RNA interference to ‘knock down’ the activity of different genes, one at a time, in ovarian cancer cells grown in the lab. Then they checked whether the loss of any particular genes affected cell division. In total the team tested 779 genes.
Most of the genes they found were the ‘usual suspects,’ which were already known to play a role in cell division. But one unexpected name turned up – SIK2.
Previously, this gene had been shown to help switch a cell’s energy sources from fat reserves back to glucose after a period of starvation, so discovering that SIK2 may be involved in cell division was surprising. But what exactly was it up to?
The researchers discovered that in the absence of the SIK2 gene, ovarian cancer cells stop dividing. To find out why, they tagged the gene with fluorescent molecules to light up the places in the cell where it’s most active.
This revealed that SIK2 is involved in the formation of the spindle – the cell’s molecular ‘scaffold.’ Knocking out SIK2 throws a spanner in the works by preventing the spindle from forming properly, making it impossible for the cells to divide.
Beating drug resistance
As we mentioned above, some cancer drugs, such as the taxane paclitaxel, work by blocking the spindle. The researchers wondered whether blocking SIK2 might also make cancer cells more sensitive to paclitaxel, since it too is involved in forming the spindle. This could help to overcome the problem of drug resistance in ovarian cancer.
To test the theory, they knocked out SIK2 in a sample of ovarian cancer cells and then treated them with paclitaxel. The results proved they were right – only half the dose of paclitaxel was needed to slow down cancer growth, suggesting that drugs targeting SIK2 could be a potent way of boosting the effectiveness of paclitaxel or other taxane drugs.
Looking further, the researchers found that SIK2 is much more active in aggressive ovarian tumors than it is in healthy cells. This is even more encouraging, as it suggests that drugs targeting the gene might be less likely to harm healthy tissue, potentially causing fewer side effects.
This discovery boosts our understanding of how ovarian cancer cells divide and lays the groundwork for new drugs to be developed targeting the SIK2 gene.
But at the moment, the researchers aren’t even at the stage of having drugs to test. The method they used to ‘turn off’ SIK2 in the lab can’t yet be adapted to give to cancer patients. So there needs to be much more work in the lab, followed by rigorous tests and clinical trials before any SlK2-blocking drugs make it into general use. And – due to the very nature of research – there’s no guarantee at this stage that the tests or trials will be successful.
So we will have to wait and see whether this surprising result can be translated into drugs with the potential to benefit cancer patients.
Illustration: The researchers used fluorescent 'tags' to track SIK2 in cancer cells. –Cancer Research UK.
Cancer Research UK News Release (08/17/10)
Abstract (Cancer Cell; 18(2), 109-121 (08/09/10))