An international team of researchers has found for the first time that a known cellular protein called SIK2 is important for cell division and that targeting it could improve response to chemotherapy in some patients with ovarian cancer.
You can read a paper on the findings, written by study senior author Dr Robert C Bast, Jr, vice president for translational research at the The University of Texas MD Anderson Cancer Center, US, and colleagues, in the 17 August issue of Cancer Cell.
This study is further evidence that using a combination of drugs, each targeting a different phase of the cell division cycle, is often a more effective way to fight cancer.
The researchers found that reducing the amount of Salt Inducible Kinase 2 (SIK2) protein in ovarian cancer cells made the cells more sensitive to paclitaxel, a commonly prescribed chemotherapy drug, increasing its ability to stop the cancer growing.
They also wrote that:
“Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serious ovarian cancers.”
Paclitaxel belongs to a family of chemotherapy drugs called taxanes which inhibit mitosis or cell division as a way to stop cancer cells proliferating.
However, only about 50 per cent of ovarian cancer patients respond successfully to taxanes, and it is not possible to find out beforehand which ones will and which ones won’t, so many patients end up being given a taxane in the hope that they are among the 50 per cent that will respond.
This is why researchers like Bast Jr and colleagues are so keen to find potential targets for drugs that enhance the ability of taxanes to interfere with cell division.
Using data and specimens from the Australian Ovarian Cancer Study, collected between 2001 and 2005, they analyzed nearly 780 pools of siRNAs (strands of genetic material involved in decoding DNA instructions) to find proteins that might change cell sensitivity to paclitaxel.
This is how they found that SIK2, a member of the AMPK family of kinases that until now was only thought to be important in resting cells, also plays a key role in the initiation of mitosis or cell division.
They showed that SIK2 influences the function of centrosomes, important cellular components that organize cellular behavior and regulate the splitting process: ” SIK2 … regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation,” they wrote.
Centrosomes have to split in order to direct the distribution of chromosomes from the mother cell into each daughter cell.
Having found a potential target, the researchers then showed that it was possible, using the known SIK2 inhibitor PKA, to change SIK2 behavior during cell division in such a way as to make ovarian cancers sensitive to paclitaxel in culture and also in tumors grafted onto lab mice.
They concluded that their findings “identify SIK2 as a plausible target for therapy in ovarian cancers”.
First author Dr Ahmed Ashour Ahmed, a former postdoctoral fellow in Bast’s lab who is now at Oxford University in the UK, said:
“The discovery that SIK2 plays a role in cell cycle regulation is groundbreaking since to date it has been linked to cellular metabolism and energy balance.”
“In addition to improving the response of some cancer to taxane, our findings add support to emerging evidence that cancer cell metabolism and mitosis functions are coupled,” he added.
Bast said further studies should now be done to investigate SIK2 and its inhibition as a potential “novel approach to improving chemotherapy for ovarian cancer”.
The Ovarian Cancer Research Fund, the National Foundation for Cancer Research, the Zarrow Foundation and the MD Anderson Ovarian Cancer Specialized Program in Research Excellence funded by the National Cancer Institute, paid for the research.
“SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer.”
Ahmed Ashour Ahmed, Zhen Lu, Nicholas B. Jennings, Dariush Etemadmoghadam, Luisa Capalbo, Rodrigo O. Jacamo, Nuno Barbosa-Morais, Xiao-Feng Le, Pablo Vivas-Mejia, Gabriel Lopez-Berestein, Geoffrey Grandjean, Geoffrey Bartholomeusz, Warren Liao, Michael Andreeff, David Bowtell, David M. Glover, Anil K. Sood, Robert C. Bast
DOI: 10.1016/j.ccr.2010.06.018
Source: University of Texas M. D. Anderson Cancer Center.
Written by: Catharine Paddock, PhD