Dysregulation of Ribosome Biogenesis and Translational Capacity Is Associated with Tumor Progression of Human Breast Cancer Cells

Abstract

Protein synthesis is a fundamental cell process and ribosomes - particularly through the ribosomal RNA that display ribozyme activity - are the main effectors of this process. Ribosome biogenesis is a very complex process involving transcriptional aswell as many post-transcriptional steps to produce functional ribosomes. It is now well demonstrated that ribosome production is enhanced in cancer cells and that ribosome biogenesis plays a crucial role in tumor progression. However, at present there is an important lack of data to determine whether the entire process of ribosome biogenesis and ribosome assembly is modified during tumor progression and what could be the potential impact on the dysregulation of translational control that is observed in cancer cells. In breast cancer cells displaying enhanced aggressivity, both in vitro and in vivo, we have analyzed the major steps of ribosome biogenesis and the translational capacity of the resulting ribosome. We show that increased tumorigenicity was associated with modifications of nucleolar morphology and profound quantitative and qualitative alterations in ribosomal biogenesis and function. Specifically cells with enhanced tumor aggressivity displayed increased synthesis of 45S pre-rRNA, with activation of an alternative preRNA synthetic pathway containing a 43S precursor and enhanced post-transcriptional methylation of specifc sites located in the 28S rRNA. While the global translational activity was not modified, IRES-initiated translation, notably that of p53 mRNA, was less efficient and the control of translational fidelity was importantly reduced in cells with increased aggressivity. These results suggest that acquisition of enhanced tumor aggressivity can be associated with profound qualitative alterations in ribosomal control, leading to reduced quality control of translation in cancer cells

Gold nanoparticles induce nuclear damage in breast cancer cells, which is further amplified by hyperthermia

“…Nucleoli are specialized compartments in the nucleus that transcribe ribosomal RNA genes and assemble ribosomal subunits [21,22]. Nucleolar hypertrophy is a hallmark of proliferating cancer cells and has been demonstrated especially in breast cancer tissue and cells [23][24][25][26][27][28]. Furthermore, nucleolar size correlates with the aggressiveness of breast tumors, and enlarged nucleoli correspond to a poor clinical outcome [23][24][25], validating the use of nucleoli as targets in cancer therapy [28].…”

“…Nucleolar hypertrophy is a hallmark of proliferating cancer cells and has been demonstrated especially in breast cancer tissue and cells [23][24][25][26][27][28]. Furthermore, nucleolar size correlates with the aggressiveness of breast tumors, and enlarged nucleoli correspond to a poor clinical outcome [23][24][25], validating the use of nucleoli as targets in cancer therapy [28]. The subcellular redistribution of the nucleolar protein fibrillarin has been linked to autoschizis in cancer cells [29]; fibrillarin was therefore selected to monitor the impact of GNPs on nucleolar organization.…”

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…Interestingly, in zebrafish, it was suggested that aberrant ribosome biogenesis through the mutation of ribosomal genes has an oncogenic potential (Amsterdam et al, 2004). In addition, a recent study showed that the enhanced progression of human breast tumor is induced by dysregulation of ribosome biogenesis and translational capacity (Belin et al, 2009).…”

Reversible induction of translational isoforms of p53 in glucose deprivation

“…1 p53 and its N-terminally truncated isoform Δ40p53 (also known as ΔN-p53 or p53/47) are translated by internal ribosome entry site (IRES)-mediated translation initiation from the same mRNA under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum (ER) stress, oncogene-induced senescence and cancer. [2][3][4][5][6][7] Thus, p53 mRNA has a dual IRES structure. 8 For their function, these IRESs rely on IRES trans-acting factors (ITAFs).…”