Hyperphosphorylation of PP2A in colorectal cancer and the potential therapeutic value showed by its forskolin-induced dephosphorylation and activation

Biochim Biophys Acta. 2014 Sep;1842(9):1823-9. doi: 10.1016/j.bbadis.2014.06.032. Epub 2014 Jul 2.


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.

Keywords: 5-Fluorouracil; Colorectal cancer; Forskolin; Oxaliplatin; PP2A-C phosphorylation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects*
  • Colforsin / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorouracil / pharmacology
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Middle Aged
  • Okadaic Acid / pharmacology
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Phosphorylation / drug effects
  • Protein Phosphatase 2 / metabolism*
  • Tumor Cells, Cultured
  • Vasodilator Agents / pharmacology*


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Organoplatinum Compounds
  • Vasodilator Agents
  • Oxaliplatin
  • Colforsin
  • Okadaic Acid
  • Protein Phosphatase 2
  • Fluorouracil