Parathyroid hormone-related protein regulates integrin α6 and β4 levels via transcriptional and post-translational pathways

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 α6β4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates α6β4 levels. We report that PTHrP regulates α6 and β4 levels via a transcriptional pathway; β4 regulation involves the NF-κB pathway. PTHrP also regulates β4 levels at the post-translational level. PTHrP inhibits caspase-3 and -7 activities. Post-translational regulation of β4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since α6 dimerizes with β4, increased β4 levels result in elevated α6 levels. Suppressing β4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin α6β4 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 α6β4 levels, may thus prove therapeutically beneficial.