Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling.

Abstract

Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and up-regulates proinvasive integrin alpha6beta4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3 as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3 cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3 and Bad. The prosurvival effects of PTHrP are accompanied by increases in the ratio of antiapoptotic to proapoptotic members of the Bcl-2 family and in levels of c-myc. PTHrP also increases nuclear factor-kappaB activity via a PI3K-dependent pathway. Integrin alpha6beta4 is known to activate PI3K. Here, we also show that knockdown of integrin alpha6beta4 negates the PTHrP-mediated activation of the PI3K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3K/Akt signaling pathway through integrin alpha6beta4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.

• Authors: Vandanajay Bhatia, Ramanjaneya V Mula, Nancy L Weigel, Miriam Falzon
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 7 Pg. 1119-31 (Jul 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19584267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Integrin alpha6beta4
• NF-kappa B
• Parathyroid Hormone-Related Protein
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Receptor, Parathyroid Hormone, Type 1
• Doxorubicin
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Analysis of Variance
• Apoptosis (drug effects)
• Cell Adhesion (physiology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cell Survival (physiology)
• Doxorubicin (pharmacology)
• Enzyme Activation
• Glycogen Synthase Kinase 3 (metabolism)
• Humans
• Integrin alpha6beta4 (metabolism)
• Male
• NF-kappa B (metabolism)
• Parathyroid Hormone-Related Protein (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Prostatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Receptor, Parathyroid Hormone, Type 1 (metabolism)
• Signal Transduction