title: Targeting peptidyl-prolyl isomerase pin1 to inhibit tumor cell aggressiveness.
abstract: OBJECTIVE
  Because the peptidyl-prolyl isomerase PIN1 interacts with multiple protein kinases and phosphoproteins into a network orchestrating the cellular response to various stimuli, there is an increasing interest in exploiting its potential as therapeutic target. In the present study, the effect of targeting PIN1 was investigated in 2 human cancer cell lines characterized by increased aggressive potential, high expression of erbB receptor family members, and defective p53.
  
  
  METHODS
  PIN1 silencing was carried out in skin squamous cell carcinoma A431 cells displaying elevated EGFR/HER1 levels and in ovarian adenocarcinoma SKOV-3 cells displaying high levels of erbB2 (HER2). Nonoverlapping siRNA duplexes targeting different regions of PIN1 mRNA were transfected in tumor cells, which were analyzed using Western blotting for the expression of selected proteins. In vivo tumorigenicity studies were carried out in athymic nude mice.
  
  
  RESULTS
  A431 and SKOV-3 cell systems were found to be a source of cells with increased aggressive potential, i.e., cancer stem cell-like cells, as defined by the capability to grow as spheres. A marked decrease of PIN1 levels and of sphere-forming capability was observed in PIN1-silenced cells. The expression of phospho-p38 decreased following PIN1 silencing in A431 and SKOV-3 cells, as well as phospho-EGFR levels in A431 - silenced cells. PIN1 inhibition prolonged latency and reduced tumor take and growth of SKOV-3 cells in nude mice.
  
  
  CONCLUSIONS
  Our results support that PIN1 may be a valuable target to hit in cancer cells characterized by increased aggressive potential, overexpression of erbB receptor family members, and defective p53.
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.affiliation: Molecular Targeting Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Albano
authors.affiliation: Molecular Targeting Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magnifico
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Corna
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.affiliation: Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015197:Carcinogenicity Tests; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse