Targeting the hypoxia-HIF-1-CXCR4 pathway by arsenic trioxide

2041 Despite the success of arsenic trioxide in the treatment of some hematological malignancies, its therapeutic role in solid tumors remains elusive. We now report that arsenic trioxide inhibits hypoxia-induced expression of the chemokine receptor CXCR4, and suppress the ability of tumor cell to metastasize. Here we have demonstrated that the mRNA and protein production of CXCR4 on HeLa cells could be significantly reduced by arsenic trioxide at the clinical achievable levels, under both normoxic and hypoxic conditions. Luciferase reporter gene assay confirms that arsenic trioxide negatively regulates hypoxia-induced CXCR4 expression in various cancer cell lines, including breast, cervical, and ovarian cancer cells. In keeping with the above, reduction of CXCR4 is essentially responsible for the arsenic-mediated inhibition of tumor migration in vitro as well as distant metastasis in vivo. Studies to date have delineated the hypoxia-HIF (hypoxia-inducible factor)-CXCR4 signaling as a pivotal pathway tuning cancer metastasis. To substantiate our finding we investigate whether arsenic trioxide negatively regulates CXCR4 expression owing to its capacity to target HIF for degradation under hypoxic conditions. Our experimental results have demonstrated that arsenic trioxide destabilized HIF-1α protein under hypoxic condition through interrupting histone deacetylase (HDAC) 1 associating with HIF-1α, thus resulting in reduction of CXCR4 expression. Further, arsenic trioxide dephosphorylated HDAC1, a process by activating PP1 phosphatase, is critically responsible for the interruption of HDAC1 binding to HIF-1α. Collectively, these results unveil Hypoxia-HIF-1-CXCR4 pathway as a novel molecular therapeutic target for arsenic trioxide. As starving tumor cells of oxygen is the major microenvironmental factor that triggers metastasis, the data presents herein may provide insight into the rational development of chemotherapeutic combinations involving arsenic trioxide as well as into molecular mechanisms of arsenic-suppressed cancer metastasis.