Parathyroid hormone related peptide (PTHrP) stimulates human colon adenocarcinoma cell proliferation through ERK 1/2, P38 MAPK and PI3K/AKT Pathways

MARTIN MJ; CALVO N; WIES MANCINI V; RUSSO DE BOLAND A; GENTILI C

Ciudad Autónoma de Buenos Aires

Congreso; XXX Reunión Anual de la Asociación Argentina de Osteología y Metabolismo Mineral (AAOMM); 2013

AAOMM

Parathyroid hormone-related peptide (PTHrP) is present in the embryo, most adult tissues and various tumors. Its expression correlates with the severity of colon carcinoma and its overexpression increases cell proliferation in certain intestinal cell lines. Previously, we demonstrated that the treatment with exogenous PTHrP (10−8 M) stimulates Caco-2 cells proliferation through ERK 1/2 MAPK pathway. In this work, we investigated if PTHrP also activate another MAPKs and the PI3K/Akt (PKB) signaling pathway, which mediates cellular responses such as proliferation and survival. Western blot analysis revealed that PTHrP treatment for 10?60 min activated p38 MAPK and Akt. The increased phosphorylation of ERK 1/2 induced by the peptide was reversed by LY 294002, a PI3K inhibitor, suggesting that the PI3K/Akt pathway is involved in the activation of this kinase. Analysis by fluorescence microscopy revealed that PTHrP induced changes in the subcellular distribution of p38 and Akt, promoting their nuclear location. The transcription factors CREB and ATF-1, known regulators of genes involved in cell proliferation, were phosphorylated by PTHrP in a time dependent manner with an early phase (10?15 min) and a second phase peaking at one hour. This effect was abolished by the inhibitors of ERK (PD 98059) and p38 MAPK (SB 203580), suggesting that both MAPKs are involved in PTHrP modulation of CREB and ATF-1 phosphorylation. Finally, we demonstrated that the proliferation of Caco-2 cells induced by the peptide is suppressed by PD 98059, SB 203580 and LY 294002 inhibitors. Altogether our results indicate that exogenous PTHrP stimulates Caco-2 cell proliferation and reveal that ERK1/2, p38 MAPK and PI3K/Akt, signaling pathways mediate the mitogenic effect of PTHrP on these intestinal cells