Nucleolar stress: is there a reverse version?

The nucleolus is a dynamic structure that has roles in various physiological and pathophysiological processes. Perturbations on many aspects of the nucleolar functions are thought to cause “nucleolar stress”, which occurs in response to a variety of chemotherapeutic drugs. The main characteristic changes of nucleolar stress include: 1) reduction of the size and volume of the nucleolus; 2) inhibition of RNA Pol I-mediated rRNA synthesis; and 3) nucleoplasmic translocation of nucleolar stress-related proteins. In studying the apoptosis-inducing effect of the natural compound lovastatin (LV) on breast cancer stem cells, we unexpectedly uncovered a novel form of nucleolar stress, which we call “reverse nucleolar stress”. In our system, the canonical nucleolus stress inducer doxorubicin caused nucleoplasmic translocation of the nucleolar protein NPM and complete abolishment of Nolc1, an NPM-interacting protein and an activator of rRNA transcription. In contrast, the reverse nucleolar stress induced by LV is manifested as a more localized perinucleolar distribution of NPM and an increase in the protein level of Nolc1. Furthermore, translocation of the ribosomal protein RPL3 from the cytoplasm to the nucleolus and increased AgNOR staining were observed. These changes characterize a novel pattern of nucleolar stress doubtlessly distinguishable from the canonical one. The functional consequences of reverse nucleolar stress are not clear at present but may presumably be related to cell death or even normalization of the stressed cell. The discovery of reverse nucleolar stress opens up a new area of research in molecular and cellular biology and might have important implications in cancer therapy.