An international team led by researchers from the Technion-Israel Institute of Technology's Rappaport Faculty of Medicine and the Technion Integrated Cancer Center (TICC) has discovered a biological pathway that plays an important role in tumor development. Published in Cell Reports, the findings could lead to cancer-fighting drugs that work by shortening the half-life of select cancer-promoting proteins known as oncoproteins.
As a rule, oncoproteins are short-lived, and play regulatory roles in "normal" (non-transformed) cells. But in cancer cells, they display enhanced stability, which gives cancer cells a longer life span. They also increase the aggressiveness of the cancer cells, which leads to tumor progression.
Led by Technion Associate Professor Amir Orian, the researchers found that RNF4 (a ubiquitin enzyme first detected in fruit flies, and later in human cancer cells) binds to these oncogenic proteins and provides them with a stabilizing structure. RNF4 itself is not an oncogenic protein, but oncogenic proteins and cancer cells are highly dependent on it.
"We have demonstrated that removing RNF4 leads to the death of the cancer cell, and hence the potential application of the discovery: the development of drugs that will inhibit the activity of RNF4 and significantly shorten the half-life of oncogenic proteins even in scenarios in which they are abnormally stabilized, thus indirectly eliminating the cancer cell," said Prof. Orian.
The researchers found an increased level of RNF4 in 30% of patients with colon cancer, and a link between that increase and reduced life expectancy in a group of breast cancer patients. Preliminary results from their lab also support the notion that RNF4 has essential roles in other types of cancer.
A twist in the ubiquitin system: from degradation and stabilization
One surprising twist to the team's findings is the role played by the ubiquitin system, which is best known as being responsible for the degradation of regulatory and damaged proteins. In this case, said Orian, it does the exact opposite - it stabilizes the cancer proteins and prevents their degradation.
Prof. Orian, a graduate of the Technion Faculty of Medicine's MD/PhD program, studied the ubiquitin system as part of his doctoral work under Distinguished Professor Aaron Ciechanover. Prof. Ciechanover won the 2004 Nobel Prize in Chemistry, together with his Technion colleague Prof. Avram Hershko, and Prof. Irwin Rose from the University of California, for the discovery of the ubiquitin system.
This system, one of the most important and vital control systems in the body, attaches a "death tag" (ubiquitin) to regulatory proteins or damaged proteins. In many cases ubiquitin tagging targets these proteins for degradation with proteasome, a multi-protein complex that operates as a protein crusher. But in this case, RNF4 and the ubiquitin system generate a unique "stabilizing" tag.
Prof. Orian is head of the Ruth and Stan Flinkman Genetic Networks Laboratory (which he established in 2005) in the Technion Faculty of Medicine, and a member of the Technion Integrated Cancer Center (TICC).
The current study was conducted by doctoral students Jane Thomas and Mona Abed (currently completing her postdoc at Genentech), as part of SignGene, a program held jointly by the Technion, Hebrew University and three research institutions in Germany, supported by the ICRF and the Flinkman-Marandy Family Cancer Genetics Research Program. Additional study participants included Dr. Rostislav Novak and Dr. Yaniv Zohar, members of the Orian lab, and the joint Atidim program of the Technion Faculty of Medicine and Rambam Healthcare Campus. The study was carried out in collaboration with Dr. Julian Heuberger and Prof. Walter Birchmeier from the Max Delbruk Center for Molecular Medicine in Berlin, Prof. Alan Schwartz from the School of Medicine at Washington University of St. Louis, and Prof. Raphael Kopan from the Department of Developmental Biology at Cincinnati Children's Hospital Medical Center.
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