Introduction: Expression of the chemokine CXCL12, also known as SDF-1, and its receptors, CXCR4 and CXCR7, are associated with prostate cancer (PC) metastasis. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) occurs in 30-80% of primary PCs, and up to 50% of PC bone metastases. In mouse models, prostate-specific deletion of PTEN leads to Akt activation and increased expression of CXCR4 and CXCL12. Moreover, the level of PTEN expression is inversely associated with prostate tumorigenesis. Additionally, HIF-1α, a hypoxia-induced transcription factor previously shown to induce expression of CXCR4, is regulated by Akt. Thus, we hypothesize that the PTEN loss-mediated activation of HIF-1α regulates the function of CXCR4 and CXCR7 receptor pathways in PC 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 developed from PTEN+/+, PTEN+/−, and PTEN−/− murine prostate epithelial cells that were isolated from the prostates of corresponding mice at 8 weeks of age, and the PTEN status in these cell lines was confirmed by genotyping and immunoblot analyses. Subsequently, these cells were treated with inhibitors of the PI3K/Akt pathway, and gene expression was determined by real time PCR.
Results: We found that loss of PTEN resulted in increased expression of CXCR4, CXCR7, and CXCL12, suggesting that loss of PTEN may play a key role in the regulation of these chemokines in prostate cancer. Additionally, expression of HIF-1α was also upregulated upon PTEN loss. Upon treatment of PTEN−/− cells with inhibitors of the PI3K/Akt pathway, the induction of CXCL12 and CXCR7 was reversed, further demonstrating the role of the PTEN regulated pathway in the expression of these genes.
Conclusions: These results suggest a molecular basis for activation of CXCL12 signaling through its receptors in prostate cancer driven by the loss of PTEN through the induction of HIF-1.
Citation Format: M. Katie Conley-LaComb, Yong Q. Chen, Hyeong-Reh C. Kim, Michael L. Cher, Sreenivasa R. Chinni. Regulation of expression of CXCL12 and its receptors CXCR4 and CXCR7 by PTEN in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C48.