Researchers have found a new way to directly inhibit the growth of cancerous cells that could have implications for patients. The scientists showed that the composition of special cellular protein factories, called ribosomes, have to be kept in a careful balance. When they are disrupted, cancer cells stop proliferating and enter into a quiet state in which they stop dividing, called senescence. These findings have been reported in Nature Cell Biology.
DNA contains the instructions necessary to build an organism. Those instructions are first copied into an intermediary molecule called RNA that eventually makes its way to the ribosome, where it is turned into protein (illustrated in the video below). "Ribosomes are complex machines composed of both RNAs and proteins that make all the proteins necessary for cells to grow," noted the senior author of the study, Gerardo Ferbeyre, a biochemistry professor at Université de Montréal (UdeM).
A population of cancer cells often exhibits unstoppable growth, which requires a huge amount of ribosomes, added Ferbyre. Cells have to orchestrate the production of not only ribosomal RNAs but also their proteins so that they will assemble in the right proportions.
"We were surprised, however, to find that if the production of ribosomal RNA-protein proportions are driven out of balance in a cancer cell, proliferation can be shut down by in a very simple and direct manner," said Ferbeyre.
The study was led by UdeM biochemistry researcher Frédéric Lessard, who worked with a team of collaborators headed by biochemistry professor Marlene Oeffinger of the UdeM-affiliated Montreal Clinical Research Institute. They showed that cancer can be stopped by inducing imbalances in ribosomal RNA and protein synthesis during senescence. The team found the mechanism behind the effect. When too much of a ribosomal protein called RPS14 was present, it could attach to an important protein that is necessary for cell growth, CDK4 or cyclin-dependent kinase-4.
Lessard suggested that this work will rapidly have an impact in the clinic. "A drug that shuts down ribosomal RNA biogenesis would immediately lead to an accumulation of ribosomal proteins outside the ribosomes, and since tumor cells make more of them, they would be preferentially affected by these kinds of drugs," Lessard said.
"The physical interaction of RPS14 with CDK4 is the most direct link between ribosome synthesis and cell proliferation regulatory pathways discovered to date. It is therefore likely a very specific way for cancer progression to be prevented,” concluded Oeffinger.