Although mechanisms of arsenic trioxide (As(2)O(3))-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 As(2)O(3) triggered apoptosis through intrinsic pathway, demonstrated that As(2)O(3) treatment significantly downregulated stathmin expression, and that decreased stathmin expression was necessary for dissipation of mitochondrial membrane potential (Deltachim), translocation of cytochrome c from mitochondria to the cytosol, and subsequent cell death. Transfection of wild type stathmin cDNA effectively delayed As(2)O(3)-mediated mitochondrial related events, however, small interfering RNA (siRNA) targeting stathmin enhanced As(2)O(3)-triggered apopotosis in cell culture and in mouse models. Furthermore, we demonstrated that As(2)O(3)-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 As(2)O(3)-treatment. These data supported a stathmin-dependent pathway of cell death in solid tumor cells induced by As(2)O(3) 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 As(2)O(3) as a therapeutic agent through combination treatment with stathmin inhibition or PI3K/Akt inhibitors.

PMID: 20657188 [PubMed - as supplied by publisher] Source: National Library of Medicine.