Modulation of molecular mechanisms involved in protein synthesis machinery as a new tool for the control of cell proliferation

Abstract

In the past years, the attention of scientists has focused mainly on the study of the genetic information and alterations that regulate eukaryotic cell proliferation and that lead to neoplastic transformation. All therapeutic strategies against cancer are, to date, directed at DNA either with cytotoxic drugs or gene therapy. Little or no interest has been aroused by protein synthesis mechanisms. However, an increasing body of data is emerging about the involvement of translational processes and factors in control of cell proliferation, indicating that protein synthesis can be an additional target for anticancer strategies. In this paper we review the novel insights on the biochemical and molecular events leading to protein biosynthesis and we describe their involvement in cell proliferation and tumorigenesis. A possible mechanistic explanation is given by the interactions that occur between protein synthesis machinery and the proliferative signal transduction pathways and that are therefore suitable targets for indirect modulation of protein synthesis. We briefly describe the molecular tools used to block protein synthesis and the attempts made at increasing their efficacy. Finally, we propose a new multimodal strategy against cancer based on the simultaneous intervention on protein synthesis and signal transduction.

Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1

“…In the last years, a series of reviews has been published on translational control giving a high impact on its role in cell growth and tumorigenesis (Clemens and Bommer, 1999;Jagus et al, 1999;Willis, 1999;Caraglia et al, 2000;Zimmer et al, 2000). Translational control no longer appears as a general and unselective control mechanism, but an increasing number of proteins were identified which are selectively regulated and which are involved in control of cell cycle and proliferation.…”

“…However, an increasing body of data is emerging about the involvement of translational processes and factors in control of cell proliferation, also indicating that protein synthesis can be an additional target for anticancer strategies (Caraglia et al, 2000). In order to characterise malignant melanoma cells, we had isolated and identified a number of genes specifically regulated in human melanoma cells as compared to normal human melanocytes (Eberle et al, 1995a(Eberle et al, ,b, 1997(Eberle et al, , 1999.…”

Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer

“…Globally, an increased protein synthesis has been related to cell growth and proliferation, linking this process with malignancy [23]. As corollary, a group of DEAD-Box proteins (DDX3X, DDX5, DDX11, DDX12, DDX49, DDX55), involved in many aspects of RNA metabolism are also differentially expressed.…”

Post-transcriptional control of the interferon system

“…The eIF5A activity is modulated by a series of post-translational modifications that culminates in the formation of the unusual amino acid hypusine. that the synthesis of this amino acid has been correlated with cell proliferation and apoptosis [83,84]. Another post-translational effect of IFN is ubiquitin conjugation, a process that targets proteins for degradation in the 26 S proteasome.…”