Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer
| Autor: | Rebeca Manso, Cristina Caramés, Jesús García-Foncillas, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo, Ion Cristóbal, Raúl Rincón |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Organoplatinum Compounds Colorectal cancer Gene Expression Antineoplastic Agents Kaplan-Meier Estimate Drug resistance medicine.disease_cause Bioinformatics Disease-Free Survival Inhibitory Concentration 50 Cell Line Tumor Internal medicine medicine Humans Neoplasm Histone Chaperones Clinical significance Molecular Targeted Therapy Protein Phosphatase 2 Aged Proportional Hazards Models Retrospective Studies Aged 80 and over Cell growth business.industry Liver Neoplasms Cancer Middle Aged medicine.disease digestive system diseases Oxaliplatin DNA-Binding Proteins Treatment Outcome Drug Resistance Neoplasm Female KRAS Colorectal Neoplasms business Transcription Factors medicine.drug |
| Zdroj: | Clinical Cancer Research. 21:347-356 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: 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). Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 21(2); 347–56. ©2014 AACR. |
| Databáze: | OpenAIRE |
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