A Cancer-dependent Protein That May Help Regulate Cancer DNA Repair

Recently, researchers from the University of Emory recently discovered that a particular protein on which cancer cells rely to protect cells from cell death may help regulate DNA repair in cancer cells. In the article, researchers elucidated how to make the protein named Mcl-1 lose function, promoting cancer cells to become more sensitive to DNA replication stress. Compounds that target the Mcl-1 protein may be a new type of anticancer drugs. The final result is published in the Journal of Clinical Investigation.

The experimental results show that this compound can effectively kill lung cancer cells in the mouse model body in combination with currently known drugs. Researchers have long known that Mcl-1 protein plays a key role in protecting cells from programmed cell death, and many types of cancer cells produce excess Mcl-1 protein.

The researchers identified another special function of the protein by observing the rise and fall of Mcl-1 protein levels in the cell cycle closely. If the cell has a serious DNA damage, that is, the DNA strand breaks, which can be repaired by cells with two methods. One of them is to copy the correct sequence from another chromosome, this process is called homologous recombination. However, this does not happen until the cells undergo chromosomal duplication. In addition, the cells try to recombine the damaged DNA in a pruning and weaving method called non-homologous end- homologous end-joining (NHEJ). The process is usually less efficient, and the researchers compared the cell dependence on the two forms of double-strand break repair to seesaws, which show a cyclical up-and-down phenomenon.

The researchers found that Mcl-1 is able to control the cells away from NHEJ but close to the process of homologous recombination. If the cells do not contain Mcl-1, they will become more sensitive to agents that induce DNA replication stress. Such as PARP inhibitors and hydroxyurea. PARP inhibitors are a class of drugs used to treat ovarian cancer and some types of breast cancer, while hydroxyurea is resistant to chronic myelogenous leukemia, squamous cell carcinoma, and sickle cell anemia. Mcl-1 does not seem to Injury X-ray induced DNA fragmentation repair process, the latter relies more on the NHEJ process.

In addition, the researchers found that a compound called MI-223 interfered with the Mcl-1 regulation of DNA repair in homologous recombination forms, as well as PARP inhibitors and hydroxyurea to kill lung cancer cells. Cancer cells become very sensitive which reply to the anti-cell death properties of Mcl-1 because cancer cells are very sensitive to the pressure of DNA replication. Therefore, Mcl-1 inhibitors may also play a role in the treatment of many other types of cancers other than lung cancer. Recently, researchers also found that Mcl-1 inhibitors may be able to effectively resist triple negative breast cancer. We will keep following the further updates on this study.