PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling

M Katie Conley-Lacomb,Pridvi Kandagatla,Michael L Cher,Allen Saliganan,Yong Q Chen,Sreenivasa R Chinni

doi:10.1186/1476-4598-12-85

M Katie Conley-Lacomb, Pridvi Kandagatla + Show 4 more

Open Access

https://doi.org/10.1186/1476-4598-12-85

Copy DOI

Abstract

IntroductionThe chemokine CXCL12, also known as SDF-1, and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) is frequently observed in cancer, resulting in the deregulation of cell survival, growth, and proliferation. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in tumor growth and bone metastasis.MethodsMurine prostate epithelial cells from PTEN+/+, PTEN+/−, and PTEN−/− (prostate specific knockdown) mice as well as human prostate cancer cell lines C4-2B, PC3, and DU145 were used in gene expression and invasion studies with Akt inhibition. Additionally, HA-tagged Akt1 was overexpressed in DU145, and tumor growth in subcutaneous and intra-tibia bone metastasis models were analyzed.ResultsLoss of PTEN resulted in increased expression of CXCR4 and CXCL12 and Akt inhibition reversed expression and cellular invasion. These results suggest that loss of PTEN may play a key role in the regulation of this chemokine activity in prostate cancer. Overexpression of Akt1 in DU145 resulted in 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. Akt1 overexpression reversed the osteosclerotic phenotype associated with DU145 cells to an osteolytic phenotype and enhanced intra-osseous tumor growth.ConclusionsThese 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. Akt1-associated CXCL12/CXCR4 signaling promotes tumor growth, suggesting that Akt inhibitors may potentially be employed as anticancer agents to target expansion of PC bone metastases.

Highlights

The chemokine CXCL12, known as stromal-derived factor-1 (SDF-1), and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood
These results suggest that loss of PTEN may play a key role in the regulation of this chemokine activity in prostate cancer
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

Summary

Introduction

The chemokine CXCL12, known as SDF-1, and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in tumor growth and bone metastasis. Chemokines are a superfamily of cytokines known to regulate the migration of cells and play a key role in the regulation of metastasis. The chemokine CXCL12, known as stromal-derived factor-1 (SDF-1), is a potent chemoattractant for hematopoetic cells [1] and activate signaling events through its two distinct receptors, CXCR4 and CXCR7. Binding of CXCL12 to CXCR4 induces trimeric G protein signaling leading to activation of the Src, PI3K/ Akt, ERK, and JNK pathways, contributing to protease production and cellular migration and invasion. CXCL12 and its receptors have been strongly linked to prostate cancer bone metastasis and are markers for poor prognosis [2,3,4,5]

Methods

Results

Conclusion