Stathmin is involved in arsenic trioxide-induced apoptosis in human cervical cancer cell lines via PI3K linked signal pathway

Although 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 showed As2O3 triggered apoptosis through intrinsic pathway, demonstrated that As2O3 treatment significantly downregulated stathmin expression, and that decreased stathmin expression was necessary for dissipation of mitochondrial membrane potential (Delta chi m), translocation of cytochrome c from mitochondria to the cytosol, and subsequent cell death. Transfection of wild type stathmin cDNA effectively delayed As2O3-mediated mitochondrial related events, however, small interfering RNA (siRNA) targeting stathmin enhanced As2O3-triggered apopotosis in cell culture and in mouse models. Furthermore, we demonstrated that As2O3-induced stathmin downregulation was mediated through Phosphatidylinositol-3-kinase (PI3K) signaling pathway, and that the PI3K inhibitor effectivly attenuated stathmin downregulation and cell apoptosis upon As2O3-treatment. These data supported a stathmin-dependent pathway of cell death in solid tumor cells induced by As2O3 treatment, and indicated that stathmin is a target of PI3K/Akt pathway in cervical cancer cells. All these results may provide a rationale for improving the efficacy of As2O3 as a therapeutic agent through combination treatment with stathmin inhibition or PI3K/Akt inhibitors.