Abstract 4088: PTEN loss mediated Akt activation promotes prostate tumor growth via CXCL12/CXCR4 signaling.
Authors: Conley-Lacomb Katie , Saliganan Allen , Chen Yong Q. , Kim Hyeong-Reh C. , Cher Michael L. , Chinni Sreenivasa R. 
Published: August 2014

Introduction: Chemokines are a family of cytokines known to regulate the migration of cells. The chemokine CXCL12, also known as SDF-1, and its receptor CXCR4 are associated with prostate cancer bone metastasis. The tumor suppressor PTEN (phosphatase and tensin homolog) is a critical regulator of growth factors and inhibitor of PI3K. Loss of PTEN is frequently observed in cancer, resulting in the deregulation of cell survival, growth, and proliferation. Previous studies have found that PTEN is lost or mutated in 30-80% of primary prostate cancer, and 50% of prostate cancer bone metastases. In mouse models of prostate cancer, it has been shown that loss of PTEN is critical for tumor initiation, and the level of PTEN expression is inversely associated with prostate tumorigenesis. Murine epithelial cells from PTEN-deficient prostate tumors also display increased expression of CXCR4 and CXCL12. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in prostate cancer progression.

Methods: Prostate-specific deletion of floxed exon 5 of PTEN was achieved by Cre recombinase expressed under the control of an androgen-responsive probasin promoter. Stable cell lines were developed from PTEN+/+, PTEN+/−, and PTEN−/− murine prostate epithelial cells isolated from prostates of corresponding mice at 8 weeks of age. PTEN status in these cell lines was confirmed by genotyping and immunoblot analyses. Human prostate cancer cell lines BPH-1, C4-2B, PC3, and DU145 were also utilized. Gene expression and invasion were analyzed in the presence or absence of Akt inhibitor. Additionally, DU145 with overexpressed HA-tagged Akt1 was also utilized in a subcutaneous injection model.

Results: Loss of PTEN resulted in increased expression of CXCR4 and CXCL12, suggesting that loss of PTEN may play a key role in the regulation of these chemokines in prostate cancer. Upon treatment of PTEN-null cells with Akt inhibitor, the induction of CXCL12/CXCR4 was reversed, further demonstrating the role of the PTEN regulated pathway in the expression of these genes. Akt inhibition also resulted in decreased invasion in response to CXCL12. Overexpression of Akt1 in DU145 resulted increased CXCR4 expression, as well as increased proliferation and cell cycle progression. Subcutaneous injection of these cells also resulted in increased tumor growth as compared to neo controls.

Conclusions: These results suggest the basis for activation of CXCL12 signaling through CXCR4 in prostate cancer driven by the loss of PTEN and subsequent activation of Akt.

Citation Format: Katie Conley-Lacomb, Allen Saliganan, Yong Q. Chen, Hyeong-Reh C. Kim, Michael L. Cher, Sreenivasa R. Chinni. PTEN loss mediated Akt activation promotes prostate tumor growth via CXCL12/CXCR4 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4088. doi:10.1158/1538-7445.AM2013-4088