Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. We have previously shown that PTHrP increases colon cancer cell proliferation, extracellular matrix adhesion, and cell-surface integrin alpha 6 beta 4 expression. Since cancer cell migration, invasion, and survival are crucial components of metastasis, and colon cancer has a high metastatic potential, in this study we used the human colon cancer cell line LoVo as a model system to study the effects of PTHrP on these parameters. PTHrP expression was modulated by stable transfection with a construct expressing PTHrP (-36 to +139). We report that PTHrP increases cell migration, invasion, and survival. PTHrP altered cell morphology, with PTHrP-overexpressing cells exhibiting increased spreading and several long protrusions. PTHrP also increased the steady-state mRNA levels of the integrin alpha 6 and beta 4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or post-transcriptional regulation of integrin alpha 6 and 134 expression. Integrin alpha 6 beta 4 activates the phosphoinositol 3-kinase (PI3K)/Akt pathway, leading to glycogen synthase kinase-3 (GSK-3) deactivation. PTHrP overexpression also led to an increase in active Akt and inactive GSK-3 levels, indicating that the PTHrP-mediated upregulation of integrin alpha 6 beta 4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion. (C) 2007 Elsevier B.V. All rights reserved.