Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Loss of the tumor suppressor PTEN or activation of chemokine receptor CXCR4 has been demonstrated to associate with OS respectively. However, the signaling mechanism underlying PTEN-mediated antitumor effect remains largely unknown, and the crosstalk between PTEN and CXCR4 in OS has not been investigated. Here, we uncover a PTEN/AKT/CXCR4 pathway nexus in highly tumorigenic and metastatic human 143B OS cells. Loss of PTEN activates AKT/CXCR4 signaling axis and regulates a series of tumor cell behaviors. Notably, ERK is inversely regulated by PTEN and its activation occurs downstream of AKT but upstream of CXCR4, suggesting this kinase to be an important mediator between AKT and CXCR4. In vivo studies show that overexpression of PTEN dramatically attenuates bone destruction, and this inhibition is associated with reduced CXCR4 expression in tumors. CXCR4 inhibitor AMD3100 also markedly suppresses tumor growth in the bone. In addition, PTEN overexpression or AMD3100 substantially inhibits tumor expansion in the lung. Our studies highlight a novel PTEN/AKT/CXCR4 signaling nexus in OS tumor growth and lung metastasis, and provide a strong rationale to consider PTEN restoration or CXCR4 blockade for the treatment of aggressive OS in humans.