title: Hyperphosphorylation of PP2A in colorectal cancer and the potential therapeutic value showed by its forskolin-induced dephosphorylation and activation.
abstract: BACKGROUND
  The tumor suppressor protein phosphatase 2A (PP2A) is frequently inactivated in human cancer and phosphorylation of its catalytic subunit (p-PP2A-C) at tyrosine-307 (Y307) has been described to inhibit this phosphatase. However, its molecular and clinical relevance in colorectal cancer (CRC) remains unclear.
  
  
  METHODS
  p-PP2A-C Y307 was determined by immunoblotting in 7 CRC cell lines and 35 CRC patients. CRC cells were treated with the PP2A activator forskolin alone or combined with the PP2A inhibitor okadaic acid, 5-fluorouracil and oxaliplatin. We examined cell growth, colonosphere formation, caspase activity and AKT and ERK activation.
  
  
  RESULTS
  PP2A-C was found hyperphosphorylated in CRC cell lines. Forskolin dephosphorylated and activated PP2A, impairing proliferation and colonosphere formation, and inducing activation of caspase 3/7 and changes in AKT and ERK phosphorylation. Moreover, forskolin showed additive effects with 5-fluorouracil and oxaliplatin treatments. Analysis of p-PP2A-C Y307 in primary tumors confirmed the presence of this alteration in a subgroup of CRC patients.
  
  
  CONCLUSIONS
  Our data show that PP2A-C hyperphosphorylation is a frequent event that contributes to PP2A inhibition in CRC. Antitumoral effects of forskolin-mediated PP2A activation suggest that the analysis of p-PP2A-C Y307 status could be used to identify a subgroup of patients who would benefit from treatments based on PP2A activators.
authors.affiliation: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain. Electronic address: ion.cristobal@fjd.es.
authors.forename: Ion
authors.initials: I
authors.lastname: Cristóbal
authors.affiliation: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Rincón
authors.affiliation: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Manso
authors.affiliation: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Madoz-Gúrpide
authors.affiliation: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Caramés
authors.affiliation: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: del Puerto-Nevado
authors.affiliation: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain. Electronic address: jgfoncillas@gmail.com.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Foncillas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D019319:Okadaic Acid / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D014665:Vasodilator Agents; D000077150:Oxaliplatin; D005576:Colforsin; D019319:Okadaic Acid; D054648:Protein Phosphatase 2; D005472:Fluorouracil
keywords: 5-Fluorouracil; Colorectal cancer; Forskolin; Oxaliplatin; PP2A-C phosphorylation