PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential
Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colo...
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| Veröffentlicht in: | Molecular cancer therapeutics 2014-04, Vol.13 (4), p.938-947 |
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| creator | Cristóbal, Ion Manso, Rebeca Rincón, Raúl Caramés, Cristina Senin, Clara Borrero, Aurea Martínez-Useros, Javier Rodriguez, María Zazo, Sandra Aguilera, Oscar Madoz-Gúrpide, Juan Rojo, Federico García-Foncillas, Jesús |
| description | Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. |
| doi_str_mv | 10.1158/1535-7163.MCT-13-0150 |
| format | Article |
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In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. 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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - administration & dosage Autoantigens - metabolism Cell Line, Tumor Cell Proliferation - drug effects Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Drug Synergism Fingolimod Hydrochloride Gene Expression Regulation, Neoplastic Histone Chaperones - metabolism HT29 Cells Humans Membrane Proteins - metabolism Propylene Glycols - pharmacology Protein Phosphatase 2 - antagonists & inhibitors Protein Phosphatase 2 - genetics Protein Phosphatase 2 - metabolism Signal Transduction - drug effects Sphingosine - analogs & derivatives Sphingosine - pharmacology Transcription Factors - metabolism |
| title | PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential |
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