TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: Relevance in human colorectal tumors

Danilo Swann Matassa, Ilenia Agliarulo, Maria Rosaria Amoroso, Francesca Maddalena, Leandra Sepe, Maria Carla Ferrari, Vinay Sagar, Silvia D'Amico, Fabrizio Loreni, Giovanni Paolella, Matteo Landriscina, Franca Esposito

Research output: Contribution to journalArticlepeer-review

Abstract

TNF receptor-associated protein 1 (TRAP1) is an HSP90 chaperone involved in stress protection and apoptosis in mitochondrial and extramitochondrial compartments. Remarkably, aberrant deregulation of TRAP1 function has been observed in several cancer types with potential new opportunities for therapeutic intervention in humans. Although previous studies by our group identified novel roles of TRAP1 in quality control of mitochondria-destined proteins through the attenuation of protein synthesis, molecular mechanisms are still largely unknown. To shed further light on the signaling pathways regulated by TRAP1 in the attenuation of protein synthesis, this study demonstrates that the entire pathway of cap-mediated translation is activated in cells following TRAP1 interference: consistently, expression and consequent phosphorylation of p70S6K and RSK1, two translation activating kinases, are increased upon TRAP1 silencing. Furthermore, we show that these regulatory functions affect the response to translational stress and cell migration in wound healing assays, processes involving both kinases. Notably, the regulatory mechanisms controlled by TRAP1 are conserved in colorectal cancer tissues, since an inverse correlation between TRAP1 and p70S6K expression is found in tumor tissues, thereby supporting the relevant role of TRAP1 translational regulation invivo. Taken as a whole, these new findings candidate TRAP1 network for new anti-cancer strategies aimed at targeting the translational/quality control machinery of tumor cells.

Original languageEnglish
Pages (from-to)1482-1494
Number of pages13
JournalMolecular Oncology
Volume8
Issue number8
DOIs
Publication statusPublished - Dec 1 2014

Keywords

  • Cell migration
  • Colorectal carcinoma
  • Ribavirin
  • Translation control
  • TRAP1
  • Wound healing

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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