The Cancer Chain Damaged by a Newly Discovered Tumor Suppressor
A recent research undergone by investigators from the M. D. Anderson Cancer Center at the University of Texas presents a new protein that suppresses tumors by identifying enzymes which support cancer and link to them molecules that act as destructors of the tumor. This paper can be found in the Molecular Cell journal.
The study was financed by grants offered by the National Cancer Institute comprising also M. D. Anderson’s Specialized Program in Research Excellence grants in ovarian, pancreatic and breast malign tumors, the Breast Cancer Research Foundation, Kadoorie Charitable Foundations, Patel Memorial Breast Cancer Endowment Fund, the National Breast Cancer Foundation and the Taiwan National Science Council.
Leading author of the study is professor Mien-Chie Hung, chair of the Molecular and Cellular Oncology department within the M. D. Anderson Cancer Center. Aiding the professor in his research were: Hsu-Ping Kuo, Mo Liu, Chao-Kai Chou, Weiya Xia, Yi Du, Jia Shen, Chun Te Chen, Longfei Huo, Ming-Chuan Hsu, Chia-Wei Li, Qing-Qing Ding, Kuo, Liu, Chou, Du, Shen, Chen, Tsai-Lien Liao, Ann-Chi Lin, Ya-Hui Chang, Shih Feng Tsai, Chien-Chen Lai and Long-Yuan Li. However, Professor Mien-Chie Hung stated that author Dung-Fang Lee conducted the laboratory experiments with regards to the IKKß. Lee`s laboratory work represented his doctoral thesis for the University of Texas Graduate School of Biomedical Sciences and he was awarded with the GSBS Alfred Knudson Jr. Outstanding Dissertation Award.
As Professor Mien-Chie Hung states the new protein is entitled KEAP1 and has the property of suppressing the growth of the malign tumors. Its enemy is entitled IKKß and represents an onco-protein which aids cancer cells in evolving in two manners, but the scientists still did not know how this protein worked. But this was until this recent study.
The team of investigators that Kelch-like ECH-associated protein 1 (KEAP1) binds itself to the IKKß and tags it with ubiquitins which are a group of molecules. These ubiquitins attacks the cancer cell proteasome system and destroys it.
Professor Mien-Chie Hung also said that low levels of KEAP1 lead to early deaths in the cases of women suffering from malign breast tumors. Moreover, the researchers discovered that the KEAP1 is either not active or has transformed functionalities in various cases of liver, lung and colon cancers.
The protein`s under-expression is linked to various types of cancer. This is why the investigators strive to understand its activation process in order to create new pills and treatments to counteract cancer. In addition, the team of scientist desire to discover if the KEAP1 can also attack other oncoproteins or just the IKKß.
Inhibiting the IkB kinase ß is one of the main concerns of Mien-Chie Hung`s team. The IKKß is the main reason in the nuclear factor ?b`s activation which is one of the regulators of gene expressions linked to the immune system`s processes, cell expansion and life, blood vanes development, cancer cells migration and tumors` spreading in the human body.
The team of scientist proved that the existence of KEAP1 stops the nuclear factor ?b signaling pathway. After this discover, the investigators moved on to a series of experiments to understand better the inhibition process. They found out that the exhausting the quantity of KEAP1 triggers the IKKß to cumulate in the human body. Carrying on with their research, the scientists found that the IKKß links to a specific location on the IKKß in order to maneuver it so as it is eaten by the proteasome.
The leading author of the study compares this process to the activity of getting toys with the metal claw at the arcades. Due to this comparison, the picture depicting the study in the Molecular Cell journal is the one showing such an action.
The ubiquitin ligase KEAP1 is aided in its mission by another protein entitled CUL3. The latter links the KEAP1 to the targeted protein.
Mien-Chie Hung`s team studied both KEAP1 and CUL3 in relation with malign tumors coming from 119 women suffering from breast cancer. Their finding was that the under-expression of the ubiquitin ligase triggered low chances of surviving the cancer fatal effects. Women enjoying a powerful activity of KEAP1 and CUL3 presented nearly 80% chances of survival in the first five years, whereas the females with a weak expression encountered a 43% rate of survival in the first five post-treatment years.
After this, the investigation team put the KEAP1’s genes to the test in 26 cancer lines from which 18 were breast tumors, four liver ones and 4 lung ones and in 119 tumors from which 17 came from breast, 78 from liver, 13 from lung and 11 from colon cancer. The researchers discovered that KEAP1 presented two major operational transformations that prevented it from acting as a tumor suppressor and stop the activity of the IKKß. These genetic transformations of the KEAP1 prevented it to link to the IKKß.
