IMPLICATION OF ERK 1/2 MAPK IN PTHrP-INDUCED SIGNAL TRANSDUCTION IN COLON ADECARCINOMA CELLS

MARTÍN, MA. JULIA; CALVO, NATALIA G; GENTILI, CLAUDIA R

Bariloche

Simposio; SISTAM 2015-The Third South American Symposium in Signal Transduction and Molecular Medicine; 2015

SISTAM

Parathyroid Hormone-related Peptide (PTHrP, also known as its tumoral analog) was initially identified through its role in humoral hypercalcemia of malignancy, one of the most frequent paraneoplastic syndromes. At present it is known that the protein is normally produced in many tissues and is recognized for its endocrine, paracrine, autocrine and intracrine modes of action. It has been observed that its expression correlates with the severity of colon carcinoma and that its overexpression increases cell proliferation in certain intestinal cell lines. Recently we obtained evidence that in Caco-2 cells, a cell line from human colorectal adenocarcinoma, exogenous PTHrP induces the phosphorylation/activation of ERK 1/2 MAPK via PI3K/Akt signaling pathway. The aim of this study was to investigate the involvement of ERK 1/2 in PTHrP-induced signal transduction in these intestinal tumor cells. We found that the hormone induces the phosphorylation and subsequent nuclear translocation of β-catenin, a protein which plays a key role in maintaining the growth and proliferation of colorectal cancer. PTHrP also induces the phosphorylation of p90 ribosomal S6 kinase (RSK), an enzyme involved in cell proliferation and migration. In addition, PTHrP-dependent β-catenin and RSK phosphorylation are reverted when ERK 1/2 activity was inhibited. To investigate the mechanism by which PTHrP activation of ERK 1/2 could be down-regulated, we focused on the dual MAPK phosphatase 1 (MKP-1). Studies with the inhibitor of ERK1/2, PD 98059, revealed that PTHrP induces MKP-1 phosphorylation through ERK1/2. Finally, our results indicate that PTHrP increases the number of live cells and induces cell migration and that ERK 1/2 inhibitor reverted the response of PTHrP-treated Caco-2 cells, suggesting that the hormone modulates the proliferation and migration of these intestinal cells via ERK 1/2 signaling pathway. The results obtained in this work expand our knowledge on the modes of action of PTHrP in intestinal tumor cells and identify, at least in part, the signaling pathways that are involved in the effects of exogenous PTHrP on colon cancer cells.