Parathyroid hormone-related protein regulates integrin ?6 and ?4 levels via transcriptional and post-translational pathways.

ABSTRACT: Parathyroid hormone-related protein (PTHrP) enhances prostate cancer (CaP) growth and metastasis in vivo. PTHrP also increases cell survival and migration, and upregulates pro-invasive integrin ?6?4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates ?6?4 levels. We report that PTHrP regulates ?6 and ?4 levels via a transcriptional pathway; ?4 regulation involves the NF-?B pathway. PTHrP also regulates ?4 levels at the post-translational level. PTHrP inhibits caspase-3 and -7 activities. Post-translational regulation of ?4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since ?6 dimerizes with ?4, increased ?4 levels result in elevated ?6 levels. Suppressing ?4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin ?6?4 levels as a function of caspase activity, and cell survival and migration. Targeting PTHrP in CaP cancer, thereby reversing the effect on caspase activity and ?6?4 levels, may thus prove therapeutically beneficial.

SUBMITTER: Bhatia V 

PROVIDER: S-EPMC3773845 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature