Once thought too conserved to be a therapeutic target for cancer, new insights could reveal ribosomal biogenesis to be an Achilles heel. Faraz K. Mardakheh gives us a breakdown…
Ribosomes are amongst the most common natural drug targets, a feature reflective of their critical function in underpinning all aspects of life. Most classes of antibiotics currently in clinical use, for example, target ribosomes in specific bacteria.
For a long time, the idea that this could be utilised in cancer was thought to be impossible. Cancer cells and their normal counterparts share a common type of ribosome – unlike bacteria and human cells. However, this view has begun to shift in recent years.
Malignant cells often ramp up ribosome production in a seemingly uncontrollable fashion, in order to meet their insatiable demands for higher protein synthesis.
In human cells, ribosome biogenesis, begins in the nucleolus. Here, large precursor ribosomal RNA molecules – which eventually form the core of ribosomes – are generated, carefully cut, folded, and assembled into the maturing ribosomal subunits along with dozens of ribosomal proteins. These maturing subunits then exit the nucleolus and nucleus, and enter the cytoplasm, where the last remaining maturation steps take place, leading to fully functional ribosomal subunits capable of carrying out protein synthesis. The entire process of ribosome biogenesis involves hundreds of molecular players, acting in a precisely choreographed manner to produce functional ribosomes.
In addition to being complex, ribosome biogenesis is amongst the most energy-intensive processes in our cells, with some estimates suggesting that more than 60% of all the ATP generated in a rapidly proliferating cell is consumed for ribosome production. It is therefore not surprising that this process is found to be under tight regulation to ensure ribosomes are only made when they are needed. However, this tight regulation seems to become universally corrupted in cancer, with malignant cells often ramping up ribosome production in a seemingly uncontrollable fashion, in order to meet their insatiable demands for higher protein synthesis. One striking side-effect of this upregulation is the enlarged nucleoli, often observed specifically in tumour cells, which pathologists have been using for over a century for cancer diagnosis.
Credit: Faraz K. Mardakheh | Cancer Research UK