• Home
  • Search Results
  • Deregulation of the PP2A inhibitor SET shows promising therapeutic implications and determines poor clinical outcome in patients with metastatic colorectal cancer.

Deregulation of the PP2A inhibitor SET shows promising therapeutic implications and determines poor clinical outcome in patients with metastatic colorectal cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research (2014-11-13)
Ion Cristóbal, Raúl Rincón, Rebeca Manso, Cristina Caramés, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo, Jesús García-Foncillas
ABSTRACT

SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC). We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC. SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P < 0.001) and progression-free survival (7.1 vs. 13.7 months; P < 0.001), and poor response to oxaliplatin-based chemotherapy (P = 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations. SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Propidium iodide, ≥94.0% (HPLC)
Sigma-Aldrich
Propidium iodide solution, solution (1.0 mg/ml in water)
Sigma-Aldrich
Trimesic acid, 95%
Sigma-Aldrich
o-Xylene, anhydrous, 97%
Sigma-Aldrich
Trimethylaluminum, 97%
Sigma-Aldrich
Oxaliplatin, powder
Sigma-Aldrich
o-Xylene, puriss. p.a., ≥99.0% (GC)
Sigma-Aldrich
Trimethylaluminum solution, 2.0 M in toluene
Sigma-Aldrich
o-Xylene, reagent grade, ≥98.0%
Supelco
o-Xylene, analytical standard
Sigma-Aldrich
Propidium iodide, ≥94% (HPLC)
Sigma-Aldrich
Trimethylaluminum solution, 2.0 M in hexanes
Supelco
o-Xylene, suitable for HPLC, 98%
Sigma-Aldrich
Trimethylaluminum, packaged for use in deposition systems
Supelco
Oxaliplatin, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
o-Xylene, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Trimethylaluminum solution, 2.0 M in heptane
Oxaliplatin, European Pharmacopoeia (EP) Reference Standard
USP
Oxaliplatin, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
β-D-Allose, rare aldohexose sugar