NONO and RALY proteins are required for YB-1 oxaliplatin induced resistance in colon adenocarcinoma cell lines

Mol Cancer. 2011 Nov 25;10:145. doi: 10.1186/1476-4598-10-145.

Abstract

Background: YB-1 is a multifunctional protein that affects transcription, splicing, and translation. Overexpression of YB-1 in breast cancers causes cisplatin resistance. Recent data have shown that YB-1 is also overexpress in colorectal cancer. In this study, we tested the hypothesis that YB-1 also confers oxaliplatin resistance in colorectal adenocarcinomas.

Results: We show for the first time that transfection of YB-1 cDNA confers oxaliplatin resistance in two colorectal cancer cell lines (SW480 and HT29 cell lines). Furthermore, we identified by mass spectrometry analyses important YB-1 interactors required for such oxaliplatin resistance in these colorectal cancer cell lines. A tagged YB-1 construct was used to identify proteins interacting directly to YB-1 in such cells. We then focused on proteins that are potentially involved in colorectal cancer progression based on the Oncomine microarray database. Genes encoding for these YB-1 interactors were also examined in the public NCBI comparative genomic hybridization database to determine whether these genes are localized to regions of chromosomes rearranged in colorectal cancer tissues. From these analyses, we obtained a list of proteins interacting with YB-1 and potentially involved in oxaliplatin resistance. Oxaliplatin dose response curves of SW480 and HT29 colorectal cancer cell lines transfected with several siRNAs corresponding to each of these YB-1 interactors were obtained to identify proteins significantly affecting oxaliplatin sensitivity upon gene silencing. Only the depletion of either NONO or RALY sensitized both colorectal cancer cell lines to oxaliplatin. Furthermore, depletion of NONO or RALY sensitized otherwise oxaliplatin resistant overexpressing YB-1 SW480 or HT29 cells.

Conclusion: These results suggest knocking down NONO or RALY significant counteracts oxaliplatin resistance in colorectal cancers overexpressing the YB-1 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Drug Resistance, Neoplasm
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / genetics*
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism
  • Humans
  • Nuclear Matrix-Associated Proteins / genetics*
  • Nuclear Matrix-Associated Proteins / metabolism
  • Octamer Transcription Factors / genetics*
  • Octamer Transcription Factors / metabolism
  • Organoplatinum Compounds / pharmacology*
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Y-Box-Binding Protein 1 / genetics*
  • Y-Box-Binding Protein 1 / metabolism

Substances

  • Antineoplastic Agents
  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • NONO protein, human
  • Nuclear Matrix-Associated Proteins
  • Octamer Transcription Factors
  • Organoplatinum Compounds
  • RALY protein, human
  • RNA-Binding Proteins
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • Oxaliplatin