Revisiting the nucleolus: from marker to dynamic integrator of cancer signaling

Abstract

Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to their oncogenic activity. Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.

Fig. 1

The role of Pol I and the nucleolus in tumor formation and therapeutic intervention. (A) A reproduction of a drawing from (). Pianese described prominent nuclear structures (blue circles) in a mammary gland carcinoma which he termed “Kernkörperchen” (literal translation: “nuclear corpuscles”) (), which we now know are nucleoli. He raised several questions regarding the abundance of these corpuscles as well as their altered size in only specific cells within the tumor (presumably advanced cancer cells), concluding with “What is the fate of Kernkörperchen?” (B) Upstream oncogenic signaling pathways such as Myc and PI3K-AKT-mTOR—as well as ΔN-netrin-1, which is present only in cancer cells—regulate rDNA transcription by modulating the abundance or the activity of Pol I transcription machinery (or both). (C) The novel small-molecule CX-5461 targets the Pol I transcription complex and may represent a new treatment for cancer. CX-5461, which induces apoptosis in cancer cells with no cytotoxic effects in normal cells, has illuminated in part how tumors can be “addicted” to the increased numbers of ribosomes required to sustain cancer cell growth and division.