Abstract
Although the mechanisms of arsenic trioxide (As2O3)-induced apoptosis have been elucidated extensively in hematologic cancers, those in solid tumors have yet to be clearly defined. In the present study, we show that As2O3 triggers apoptosis through the intrinsic pathway and significantly downregulates stathmin expression. Decreased stathmin expression is necessary for the dissipation of mitochondrial membrane potential (Δ ψm), the translocation of cytochrome C from the mitochondria to the cytosol, and subsequent cell death. Overexpression of wild type stathmin effectively delays As2O3-mediated mitochondrial events. Conversely, expression of a small interfering RNA (siRNA) targeting stathmin enhances As2O3-triggered apoptosis in cell culture and in mouse models. Furthermore, we demonstrate that As2O3-induced stathmin downregulation is mediated through the phosphatidylinositol-3-kinase (PI3K) signaling pathway, and that a PI3K inhibitor effectively attenuated stathmin downregulation and cell apoptosis upon As2O3-treatment. These data support a stathmin-dependent pathway of As2O3-mediated cell death in solid tumor cells, and indicate that stathmin is a target of the PI3K/Akt pathway in cervical cancer cells. All these results may ...Continue Reading
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