Format

Send to

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

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

Author information

1
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.
2
Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
3
Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
4
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.

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.

KEYWORDS:

5-Fluorouracil; Colorectal cancer; Forskolin; Oxaliplatin; PP2A-C phosphorylation

PMID:
24997451
DOI:
10.1016/j.bbadis.2014.06.032
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center