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

Authors

M Conley-LaComb, Wayne State University School of MedicineFollow
Allen Saliganan, Wayne State University School of MedicineFollow
Pridvi Kandagatla, Wayne State University School of MedicineFollow
Yong Q. Chen, Wake Forest UniversityFollow
Michael L. Cher, Wayne State University School of MedicineFollow
Sreenivasa R. Chinni, Wayne State University School of MedicineFollow

Document Type

Article

Abstract

Abstract

Introduction

The 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.

Methods

Murine 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.

Results

Loss 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.

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. 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.

Disciplines

Oncology | Pathology | Urology

Recommended Citation

Conley-LaComb et al.: PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/ CXCR4 signaling. Molecular Cancer 2013 12:85.