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 alpha6beta4 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 alpha6 and beta4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or post-transcriptional regulation of integrin alpha6 and beta4 expression. Integrin alpha6beta4 activates the phosphoinositol 3-kinase (PI3-K)/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 alpha6beta4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion.
Shen
Xiaoli
X
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 10th and Market Streets, Galveston, TX 77555, United States.
Mula
Ramanjaneya V R
RV
Evers
B Mark
BM
Falzon
Miriam
M
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D044162:Parathyroid Hormone-Related Protein; D051057:Proto-Oncogene Proteins c-akt