Highlights •URI/OGT/PP1γ forms a functional heterotrimeric complex in cancer cells •Glucose depletion phosphorylates URI at Ser-371, releasing PP1γ to inhibit OGT •OGT inhibition reduces c-MYC, promoting cancer cell survival upon metabolic stress •URI (S371A) increases O-GlcNAcylation, c-MYC levels, and hepatocarcinogenesis
New research provides important clues that might help understand the resistance to drugs that ‘starve’ tumors, and also how cancer cells manage to survive in the center of the tumor mass, where barely any blood vessels can reach. CNIO resesarchers have discovered a group of proteins that actually act as a switch: when food -glucose- is available, tumour cells use a particular biochemical path to survive and continue to proliferate; when there is no glucose, the switch triggers a different path to achieve the same goal, namely the survival of the tumour cells.
It is urgent to understand the resistance to anti-angiogenic agents, one of the most widely-used anticancer drugs in recent years and whose effectiveness is based on preventing the growth of the blood vessels that supply the tumour, thus starving the cancer cells of nutrients.
This is a sophisticated system composed with 3 proteins: URI protein (which act as the switch), OGT and c-Myc. c-Myc is a well known oncogene, i.e. it promotes cell proliferation and survival. However, Djouder’s group has discovered that c-Myc protein levels matter for cancer cell survival upon nutrient stress.
Sequence of events: URI controls OGT activity. OGT senses and utilizes the glucose to control c-Myc levels. When glucose is present, OGT uses glucose to stabilize c-MYC levels which fulfils its role as an oncogene. When, on the contrary, cells face a situation of glucose shortage, URI becomes a potent inhibitor of OGT and decreases OGT activity which reduces its glucose consumption. This leads to c-Myc degradation. c-Myc is thus eliminated. Thus in the absence of glucose the survival of the cell depends on URI which has oncogenic activities.
Our findings suggest an important glucose-sensing mechanism in which URI acts as a rheostat controlling OGT activity and therefore c-MYC levels, conferring selective traits that allow cancer cells to tolerate severe metabolic stress and survive under selective pressures imposed by environmental challenges.” This mechanism can be of general importance in tumorigenesis and may explain how cancer cells exposed to glucose deficiency can expand instead of regressing.”
This finding is still far from having any practical application as one of the obvious strategies, such as hijacking the action of URI is simply not possible to date. URI is a protein whose functions are not yet sufficiently known. Nabil Djouder and his group at the CNIO will continue to study it. http://www.cnio.es/ing/publicaciones/cnio-researchers-have-discovered-a-mechanism-that-allows-cancer-to-survive-without-glucose
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