Abstract 1969: Mapping the cross talk between parathyroid hormone related protein (PTHrP) and Integrins α6 and β4 in prostate cancer cells

Abstract

Abstract Prostate carcinoma is a leading cause of cancer deaths in men in the United States. An estimated 217,730 new cases and 32,050 deaths from prostate cancer have been reported in 2010 by the National Cancer Institute. For a cancer cell to become malignant it must adopt mechanisms to escape and survive outside its original environment, thus avoiding apoptosis. Parathyroid hormone-related protein (PTHrP) is among the many factors that contribute to this pro-survival state. The mechanisms through which PTHrP affects cell malignancy are not well understood. Our previous studies have shown that PTHrP increases cell-surface levels of integrin α6β4 in prostate cancer cells. Over-expression of integrin α6β4 correlates with increased tumor invasion and metastasis. Integrin α6β4 also acts as a signaling molecule that activates anti-apoptotic phosphoinositide 3-kinase (PI3K) signaling pathways. The mechanism through which PTHrP increases α6 and β4 integrins levels is not clear. We report that in PTHrP over-expressing prostate cancer cell lines (C4-2 and PC-3), the activity of α6 and β4 promoters is increased by ∼ 2.5 fold. We have also found increased NF-κB promoter activity in C4-2 and PC-3 cell lines as a result of PTHrP over-expression. Identification of elements within the integrin α6 and β4 gene promoters that are regulated by PTHrP signaling can provide valuable information regarding the mechanism of the PTHrP action in cancer cell survival and invasion. PTHrP also regulates α6 and β4 protein levels via a post-translational pathway, since the PTHrP protein half-life is higher in PTHrP-over expressing cells in comparison to empty vector control cells. This effect is mediated via the proteasome pathway, as ubiquitinated α6 and β4 levels are reduced in PTHrP over-expressing cells. Our future goals are to map the regulatory elements like NF-κB in the α6 and β4 integrin promoters that are regulated by PTHrP, and to identify the pathways via which PTHrP regulates the proteasome pathway. This might help understand the mechanism through which PTHrP acts in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1969. doi:10.1158/1538-7445.AM2011-1969