The PEA-15/PED Protein Regulates Cellular Survival and Invasiveness in Colorectal Carcinomas

Cancer Lett. 2013 Jul 28;335(2):431-40. doi: 10.1016/j.canlet.2013.02.053. Epub 2013 Mar 7.

Abstract

The PEA-15/PED (phosphoprotein enriched in astrocytes 15kD/phosphoprotein enriched in diabetes) protein is a multifunctional phosphoprotein involved in various signaling pathways which determine survival, proliferation, and migration of cancer cells. Here, we investigated the expression and cellular functions of PEA-15 in colorectal carcinoma (CRC). PEA-15 is expressed in the majority of human CRC, predominantly in well differentiated tumor areas. A tissue microarray analysis of 1262 human CRC specimens from the DACHS study showed that PEA-15 expression is significantly associated with a low pT stadium as defined by limited invasion into the bowel wall. Moreover, patients with PEA-15-positive CRC exhibited a significantly longer tumor-specific survival time. To investigate the functional relevance of PEA-15 expression on a cellular level, we over-expressed PEA-15 in several CRC cell lines. Increased expression of PEA-15 resulted in a strong inhibition of clonogenicity, proliferation, and invasiveness of CRC cells. These effects were associated with a PEA-15-dependent down-regulation of integrin αvβ5 as well as with elevated levels of the phosphorylated MAP kinase ERK1/2. Moreover, expression of PEA-15 resulted in significant protection from cell death induced by cytotoxic drugs (5-FU, cisplatin), by the death ligand TRAIL, or by serum withdrawal. In conclusion, the PEA-15 protein regulates invasiveness, proliferation, and apoptosis resistance in CRC cells. PEA-15 might play an important role in chemoresistance, progression and metastasis in CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cisplatin / pharmacology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fluorouracil / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Receptors, Vitronectin / biosynthesis
  • Signal Transduction
  • Tissue Array Analysis

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • PEA15 protein, human
  • Phosphoproteins
  • Receptors, Vitronectin
  • integrin alphaVbeta5
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin
  • Fluorouracil