Scientists from The Institute of Cancer Research, London, found that HPV protein E6 caused ovarian cancer cells to grow more slowly but changed the way they produced energy, which could confer them with a survival advantage.
Ovarian cancer cells infected with the E6 protein also migrated more quickly, according to the study, funded by Cancer Research UK and the EPSRC Cancer Imaging Centre at the Institute of Cancer Research (ICR), with additional funding from Marie Curie Action.
The findings, published in the journal Cellular Physiology and Biochemistry, might help explain why some forms of HPV infection can cause cancer to develop.
The DNA virus HPV is one of the leading infectious causes of cancer and increases a woman’s risk of developing cervical cancer, but how exactly the virus does this is still unclear. Four out of five women will be infected with HPV at some time in their life, but only some infections, and with some types of the virus, lead to cancer.
HPV infection introduces new genes to cells in the body, which express proteins that increase a woman’s chance of developing cancer. Previous research has shown that the HPV viral protein E6 manipulates proteins in cells that regulate cell division, leading to uncontrolled growth. But HPV infection causes cancer cells to produce several proteins, so it’s unclear what role E6 plays in the changes that occur in infected cancer cells.
Scientists at The Institute of Cancer Research (ICR) took a pair of ovarian cancer cell lines, of which one cell line expressed the HPV protein E6, but were otherwise identical. They let the cells grow for four days and used magnetic resonance spectroscopy to monitor the levels of metabolic compounds linked to growth for cells with (E6+), and without (E6-) the protein.
They anticipated that ovarian cancer cells containing E6 would express lower amounts of a protein called p53, a key regulator of cell cycle processes, leading to uncontrolled growth, but what they found surprised them.
They saw that E6+ cells did express lower levels of P53 than ovarian cancer cells without the protein, but instead of increasing their growth rate, the E6+ cells grew more slowly than E6- cells.
After four days the E6+ cells took 22 hours to double in number, compared with 19.5 hours for E6- cells. This slowdown in growth was accompanied by changes in metabolite levels, with reduced energy production from glucose in E6+ cells.
The researchers saw that energy production was initially maintained in E6+ cells by increased metabolism of glutamine, a characteristic of cancer cells. By the fourth day, both glutamine and glucose metabolism had risen in E6+ cells.
Cancer cells already have mechanisms that give them growth advantages over normal cells, but they found that E6+ cells could also migrate more quickly and form larger cell colonies than E6- cells. The results suggest that alterations in cellular mechanisms by the E6 viral protein enable ovarian cancer cells to develop more aggressive and invasive characteristics.
Dr Yuen-Li Chung, senior staff scientist in the Magnetic Resonance team at The Institute of Cancer Research, London, said: “It’s thought that the E6 protein blocks key tumour-suppressing genes and promotes cellular proliferation, increasing the chance of malignancy, so we were very surprised to see that E6 caused ovarian cancer cells to grow more slowly instead. We repeated our experiment many times to make sure we were confident in our findings, but we saw the same results.”
Professor Nandita deSouza, Professor of Translational Imaging at The Institute of Cancer Research, London, and Honorary Consultant at The Royal Marsden, said: “HPV infection is a leading factor in cervical cancer and causes cells to express a range of different proteins, but by adding the HPV viral protein E6 to ovarian cancer cells, we’ve been able to see the effect of just one protein for the first time, and the outcomes were completely unexpected.
“While the viral protein E6 caused ovarian cancer cells to grow more slowly, we found that E6-infected cells were more invasive and migrated faster than cells without the protein. More research is required and we need to test this in more types of cancer, but we think that E6 could confer these cells with a survival advantage over other cells and begin to explain how HPV causes cancer.”
- Yuen-Li Chung, Eszter Nagy, Dominik Zietkowski, Geoffrey S. Payne, David H. Phillips, Nandita M. deSouza. (2013) Molecular and Metabolic Consequences Following E6 Transfection in an Isogenic Ovarian Cell Line (A2780) Pair. Cell Physiol Biochem. 32:1460-1472 DOI: 10.1159/000356583