title: The PEA-15/PED protein regulates cellular survival and invasiveness in colorectal carcinomas.
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.
authors.affiliation: Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Funke
authors.forename: Judith
authors.initials: J
authors.lastname: Lehmann-Koch
authors.forename: Michèle
authors.initials: M
authors.lastname: Bickeböller
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Tagscherer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Grund
authors.forename: Marco
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019030:Receptors, Vitronectin / Q000096:biosynthesis; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin; D005472:Fluorouracil