Checkpoint Proteins Enable Resistance of Cancer Cells Against Drugs
Scholars from the Salk Institute for Biological Studies discovered that checkpoints for the cellular life cycle enable damaged cells to stop dividing and stall them. However, even if this molecular stop generated by the cell cycle checkpoints stops the cells, cancer ones manage to pass over it and become immune to the treatment with various types of chemotherapy. This study can be found in Molecular Cell, the August issue. The research shows cases of how the checkpoint`s actions can stall and even decrease the dividing power of cancer cells by damaging their internal DNA.
The research team was led by Professor Doctor Tony Hunter from the Molecular and Cell Biology Laboratory and was aided in his study by: John Brognard, Zhongsheng You, Aaron Aslanian, Chris Coughlin, Robert T. Abraham, Marisa Dolled-Filhart and Gerard Manning.
As Professor Hunter states: “A lot of progress has been made in understanding the molecular details of checkpoint activation, but checkpoint termination, which is essential for the resumption of cell cycle progression, is less well understood.” This is why they undertook the study, in order to gather more information about this process and find out how they can diminish the resistance to chemotherapy of the cancer cells. By doing this, they would later be able to develop treatments with smaller side-effects based on the checkpoint exit mechanism. Researcher You-Wei Zhang states that if the doctors would be able to scan tumors to discover their resistance to chemotherapy, they would be able to adjust the treatment.
When the DNA is damaged, eukaryotes which copy DNA enable the checkpoint for DNA damaged cells to stall the process, allowing them time to recover from the interruption. In case the repairs do not take place, the cells may die or mutate into cancer. The main actor in this process is the Chk1 checkpoint protein. It reacts to hypoxia, cancer drugs that strive to damage the DNA of tumor cells and radiations. These factors affect the evolution of Chk1 and, in time, lead to the protein`s degradation. However, researchers have not discovered yet what triggers the disposal of Chk1 by the protein degradation mechanism.
You-Wei Zhang studied this protein and found out that when it is activated it brings to light a degron which is a string of amino acids. The degron attracts F box protein 6 which marks Chk1 with an enzyme group that degrades the proteins. This eliminates the Chk1 proteins and enables the cell life cycle to get back to the progression process. In the case of a long period of replication stop, the action of the enzyme complex will resume to kill the damaged cells. However, there are malign cells that counteract the effect of the enzymes and still manage to replicate. Doctor Hunter states: “Camptothecins are FDA-approved cancer drugs that induce replication stress and stop cancer cells dividing, but their clinical antitumor activity is very limited by the relatively rapid emergence of drug resistance, and the mechanisms are poorly understood. We wondered whether defects in the Chk1 destruction machinery might allow cells to ignore the effects of camptothecin and similar drugs used for chemotherapy.”
Researcher Zhang discovered by looking at cancer cell lines cultures and tissues from breast cancers that the levels of F box protein 6 were low when protein Chk1 was present in a large number and vice versa. Moreover, he proved that the two out of three camptothecin-resistant malign cellular lines located in the cell samples from the National Cancer Institute showed the same deficiencies in the degradation of Chk1 induced by camptothecin. This was the result of the small levels of F box protein 6. You-Wei Zhang states: “Chk1 and Fbx6 clearly play an important role for the regulation of the response to chemotherapy. One day, they could become an important prognostic marker that predicts patients’ responsiveness to drugs such as irinotecan, platinum compounds, and gemcitabine, while Chk1 inhibitors might increase tumor cells’ sensitivity to these drugs.” This shows that this kind of therapy may reduce and even annihilate the chemotherapy resistance of the malign cell. Moreover, it could mean that the quantities of cancer drugs given to ill patients may be reduced, therefore, minimizing their secondary and negative side-effects.
