Oxaliplatin treatment causes downregulation of nucleolar and ribosomal proteins decrease

Introduction

Oxaliplatin is a widely used anticancer drug. It is part of treatment regimens for colorectal and pancreatic cancers, but it is tested in esophageal, biliary tract, gastric or hepatocellular cancers as well. Contrary to this wide application, there is only limited amount of information about oxaliplatin mechanism and response to treatment.

Materials/methods

We have performed whole-cell proteomic study to obtain cellular response induced by oxaliplatin. For this purpose we have treated CCRFCEM cell line by 5xIC50 (29.3 μM) for half-time to caspase activation (240 min). Those cells were mixed with SILAC labeled untreated cells and analyzed using high-resolution mass spectrometry approach.

Results and conclusions

We have identified 4139, 4132 and 3905 proteins from three biological replicates. From this amount 70 proteins were significantly downregulated and 20 proteins upregulated in at least two replicates. Upregulated proteins are involved mainly in DNA damage response, which is the most significant effect of platinum drugs. Downregulated proteins split into two fractions. One fraction was proteins involved in RNA processing or proteins of processome of both ribosomal subunits. Downregulation of those proteins shows to ongoing nucleolar stress. Second fraction consisted of several ribosomal proteins. This should be sign of ribosomal stress. Nucleolar and ribosomal stress are stress responses manifesting by nucleolar shrinkage or and by inhibition of ribosomal biogenesis. Cellular response to oxaliplatin is thus DNA damage response, which triggers nucleolar and subsequent ribosomal stress. Such stress response has been found in the past in the case of variety of chemical and physical stressors, e.g. actinomycin D, etoposide or UV irradiation.

This work was supported by grants LF_2015_031 and by the National Sustainability Programme (LO1304).