Parathyroid hormone-related protein regulates integrin ¦Á6 and ¦Â4 levels via transcriptional and post-translational pathways

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• 作者：Vandanajay Bhatia^a ; Ramanjaneya V.R. Mula^a ; Miriam Falzon^a ; ^b ; ^{mfalzon@utmb.edu}
• 关键词：PTHrP ; Integrin ¦Á6¦Â4 ; Caspase ; Apoptosis ; Migration
• 刊名：Experimental Cell Research
• 出版年：2013
• 出版时间：10 June, 2013
• 年：2013
• 卷：319
• 期：10
• 页码：1419-1430
• 全文大小：1672 K

文摘

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 ¦Á6¦Â4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates ¦Á6¦Â4 levels. We report that PTHrP regulates ¦Á6 and ¦Â4 levels via a transcriptional pathway; ¦Â4 regulation involves the NF-¦ÊB pathway. PTHrP also regulates ¦Â4 levels at the post-translational level. PTHrP inhibits caspase-3 and -7 activities. Post-translational regulation of ¦Â4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since ¦Á6 dimerizes with ¦Â4, increased ¦Â4 levels result in elevated ¦Á6 levels. Suppressing ¦Â4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin ¦Á6¦Â4 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 ¦Á6¦Â4 levels, may thus prove therapeutically beneficial.