Parathyroid hormone related peptide (PTHrP) stimulates mitogenic pathways of MAP kinases in cells of human colon cancer

MARTÍN, MA. JULIA; CALVO, NATALIA G; RUSSO DE BOLAND, ANA; GENTILI, CLAUDIA R

Buenos Aires

Congreso; XXIX Reunion Anual AAOMM; 2012

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. Recently, the protein was found to be distributed in most fetal and adult tissues. It has been observed that their expression correlates with the severity of colon carcinoma and that its overexpression increases cell proliferation in certain intestinal cell lines. However, so far the role of PTHrP in Caco-2, a cell line derived from human colorectal adenocarcinoma, is not known. This study examined, for the first time, whether PTHrP induces proliferation of Caco-2 cells and whether it regulates the MAP kinases (ERK1/2, JNK1/2, p38 MAPK) signaling related to events of cell proliferation. Using different cell proliferation assays we found that PTHrP (10− 8 M) increased cell proliferation compared to the control and, in a time dependent manner, being maximal response at 5 and 6 days of treatment. Furthermore, analysis by Western blot revealed that PTHrP (1?48 h) induced phosphorylation and activation of ERK 1/2 and increased the levels of c-Myc protein, a transcription factor that regulates genes involved in cell proliferation. However, at the times studied, no significant changes were observed in the phosphorylation of JNK isoforms or in the protein expression of both the α isoform of p38 and ERK 1/2. Moreover, immunocytochemistry assays revealed that PTHrP induces the subcellular redistribution of the ERKs. Furthermore, a specific inhibitor of MEK, the kinase ?upstream? of ERK 1/2, decreased PTHrP-induced increased of viable cells. These results suggest that in Caco-2 intestinal cells PTHrP promotes the activation and subcellular redistribution of ERK 1/2, increases the expression of c-Myc and the proliferation of intestinal cells through the signaling pathway of ERK 1/2.