There are some very fickle molecules that sometimes boost tumor cell growth, and yet at other times suppress their growth. A new study has elucidated how this works, and the researchers involved have dubbed these molecules as ‘Jekyll-and-Hyde’ proteins. A collaborative effort from Oxford University Singapore and the University of Texas MD Anderson Cancer Center has found that the protein E2F has involvement with the vast majority of cancers. The researchers were able to determine the dual nature of this protein and how this information can be used in new development of potent drugs. Researchers at Oxford University and MD Anderson have discovered how these proteins change into “Mr Hyde’ resulting in the death of cancer cells.
According to Professor Nick La Thangue of the Department of Oncology at Oxford University, “Subtle changes in terms of the chemistry of the protein have dramatic and polar opposite effects on the tumor cell, either allowing them to continuously grow or switching them to cell death mode. We are excited by this new discovery, which provides a new and very important approach to developing new types of cancer drugs. The mechanism for switching a key protein is very novel. Nothing else I’ve come across behaves like it. Subtle changes in terms of the chemistry of the protein have dramatic and polar opposite effects on the tumor cell, either allowing them to continuously grow or switching them to cell death mode. We have much work to do.”
Keep in mind that cells in the body go through cycles of growth and division, pauses, and death in a highly regulated manner. Cancer involves the breakdown of these controls, leading to unlimited expansion of the cells in a growing tumor. Under abnormal conditions, E2F oversees go out of control and the cells keep growing. This system is confusing in that in other occasions, E2F plays a protective role and removes damaged cells. When normal cells suffer damage, E2F is involved in switching the cell towards cell death in a process called apoptosis. This helps prevent the build up of abnormal cells, their DNA errors and the development of cancer.
Now, this is the first time that this dual Jekyll-and-Hyde nature of E2F that the researchers have observed can be explained.
The researchers have discovered that E2F is an important switch that determines cell fate. As Dr. Jekyll, when DNA damage is detected, it leads to cell death. As Mr. Hyde, it switches on cell growth and proliferation – and in most if not all cancers, it is this function of E2F that becomes out of control. The researchers have found that two enzymes compete with each other to attach to make a molecular tag on different parts of the E2F protein. As it turns out, the binding in one position causes E2F to activate cell death (apoptosis) and binding to another position sees E2F as a boost in cell growth and proliferation.
According to professor La Thangue, It’s as if there’s an angel and a devil competing to get on each shoulder of the protein. Whichever one gets the upper hand is able to whisper in the ear of the protein and tell it what it should do. With the molecular flag on one shoulder, E2F goes into cell kill mode. With the flag on the other, it goes into cell growth mode. The challenge is to mimic this process with drugs, and reinstate the death pathway in tumor cells.” Cancer cells tend to have E2F stuck with the flag boosting growth and division, driving the tumors growth. Researcher were able to find another protein in the cell which looks for the presence of this flag. According to La Thange, “Blocking this protein means the devil’s whispers never get heard and E2F doesn’t transform into Mr Hyde. Instead, E2F switches over to cell-death mode and the cancer cells die out.”
The interesting thing is that La Thange and colleagues have identified compounds (drug candidates) that do exactly what is in the system. Importantly, Dr Shunsheng Zheng, first author of the study and a graduate student on the joint A*STAR-University of Oxford DPhil scholarship program, said: “E2F is a tricky protein to work with. Normal cells use it for growth, cancer cells need it for hyper growth, but too much of it seems to drive cancer cells into suicidal mode.” Obviously, balance is crucial.
According to Dr Kat Arney, science information manager at Cancer Research UK, which partly funded the work, said: ‘Cancer is a complex biological problem, and getting to grips with the molecules that drive it is essential if we’re to find new cures. Although there’s a lot more work to be done before this new discovery could become a treatment for patients, this research is an important step forward in understanding E2F’s ‘split personality’ in both driving and destroying cancer cells.”