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Targeting peptidyl-prolyl isomerase pin1 to inhibit tumor cell aggressiveness

Abstract

Purpose

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.

Tumori 2016; 102(2): 144 - 149

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000471

Authors

Giovanni L. Beretta, Michelandrea De Cesare, Luisa Albano, Alessandra Magnifico, Nives Carenini, Elisabetta Corna, Paola Perego, Laura Gatti

Article History

Disclosures

Financial support: Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy.
Conflict of interest: None of the authors has conflict of interest with this submission.

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Authors

Affiliations

  •  Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
  •  Molecular Targeting Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy

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