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 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.
Authors' Affiliations: Translational Oncology Division, Health Research Institute and Oncology Department, University Hospital "Fundación Jiménez Díaz," Autonomous University of Madrid; Pathology Department, IIS "Fundación Jiménez Díaz," Madrid, Spain; and Medical Oncology Department, University Hospital of Vigo, Vigo, Spain.
Ion
I
Cristóbal
Rebeca
R
Manso
Raúl
R
Rincón
Cristina
C
Caramés
Clara
C
Senin
Aurea
A
Borrero
Javier
J
Martínez-Useros
María
M
Rodriguez
Sandra
S
Zazo
Oscar
O
Aguilera
Juan
J
Madoz-Gúrpide
Federico
F
Rojo
Jesús
J
García-Foncillas
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001324:Autoantigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D000068876:Fingolimod Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011409:Propylene Glycols; C513473:SET protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine