Abstract
Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) alpha. We compared the effects of vanadate to PFTalpha and PFTmicro, an inhibitor of transcription-independent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcription-independent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis.
Highlights
Acute radiation lethality is largely caused by the injury of sensitive organs, the bone marrow and gastrointestinal tract; these injuries are known as hematopoietic syndrome and gastrointestinal syndrome, respectively [1]
We found that the phosphorylation of Akt, a known antiapoptotic signal relayed through phosphatidylinositol 3-kinase (PI3K) and DNA-dependent protein kinase [28], is increased by vanadate; the PI3K inhibitor www.aacrjournals.org
To ascertain whether vanadate or PFTα suppressed p53independent mitochondrial dysfunction, we investigated their effects on the anisomycin-induced loss of Δψm and on the apoptosis induced by expressing exogenous Bax (Supplementary Fig. S3D)
Summary
Acute radiation lethality is largely caused by the injury of sensitive organs, the bone marrow and gastrointestinal tract; these injuries are known as hematopoietic syndrome and gastrointestinal syndrome, respectively [1]. In these organs, genotoxic stress induces massive apoptosis, which causes some of the adverse side effects of anticancer radiation therapy and chemotherapy that frequently restrict their use [2]. New radioprotectors that inhibit apoptosis have been introduced. These drugs are intended to minimize the apoptosis-inducing sensitivity of target organs.
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