Although gold compounds are now recognized as promising anticancer agents, so far only gold(I) derivatives have been investigated for this purpose, whereas the use of gold(III) complexes has been hampered by their poor stability under physiological conditions. We have therefore carried out studies on selected gold(III) anticancer agents, showing enhanced stability due to the presence of chelating dithiocarbamato ligands. We found that they induce cancer cell death through both apoptotic and nonapoptotic mechanisms. They also inhibit thioredoxin reductase activity, generate free radicals, modify some mitochondrial functions, and increase ERK1/2 phosphorylation. Based on our results, we propose and discuss a working model suggesting that deregulation of the thioredoxin reductase/thioredoxin redox system is a major mechanism involved in the anticancer activity of the investigated gold(III)-dithiocarbamato complexes.

Human T cell leukemia virus type 1 encodes an ''accessory'' protein named p13 II that is targeted to mitochondria and triggers a rapid flux of K ؉ and Ca 2؉ across the inner membrane. In this study, we investigated the effects of p13 II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13 II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13 II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13 II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13 II cell lines exhibited an enhanced response to Ca 2؉ -mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13 II -expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13 II as a negative regulator of cell growth and underscore a link between mitochondria, Ca 2؉ signaling, and tumorigenicity.apoptosis ͉ calcium signaling ͉ tumorigenicity ͉ retrovirus H uman T cell leukemia virus type 1 (HTLV-1) possesses a complex genome that codes for Gag, Pol, Env, Tax, Rex, and a number of ''accessory'' proteins (1-4). Although the function of the accessory proteins has not yet been elucidated completely, they elicit an immune response in HTLV-1 infected individuals (5) and are required for efficient viral propagation in an animal model (6).One of the HTLV-1 accessory proteins, p13 II , accumulates in mitochondria by means of an amphipathic mitochondrial targeting signal and disrupts mitochondrial morphology (7). Biochemical analyses showed that p13 II is inserted in the inner mitochondrial membrane and alters mitochondrial conductance to Ca 2ϩ and K ϩ , leading to swelling and collapse of inner mitochondrial membrane potential (8).These effects suggest that p13 II might alter key mitochondrial functions such as energy production, redox status, and apoptosis, which could in turn disrupt the balance between cell death and proliferation. In this study, we investigated the impact of p13 II on cell growth in vitro and tumor growth in vivo by using the rat embryo fibroblast (REF) transformation model and cell lines expressing p13 II . Results showed that p13 II -expressing cells exhibit reduced tumorigenicity in vivo and slower proliferation at high density in vitro. p13 II -expressing cells also display perturbations in signal transduction pathways depending on Ca 2ϩ homeostasis. Materials and MethodsGeneration of HeLa Tet-On Cell Lines Expressing p13 II . The doxycyclininducible p13 II expression plasmid pTRE-p13 II -AU1 was constructed by inse...

The present study investigated the function of p13, a mitochondrial protein of human T-cell leukemia virus type 1 (HTLV-1). Although necessary for viral propagation in vivo, the mechanism of function of p13 is incompletely understood. Drawing from studies in isolated mitochondria, we analyzed the effects of p13 on mitochondrial reactive oxygen species (ROS) in transformed and primary T cells. In transformed cells (Jurkat, HeLa), p13 did not affect ROS unless the cells were subjected to glucose deprivation, which led to a p13-dependent increase in ROS and cell death. Using RNA interference we confirmed that expression of p13 also influences glucose starvation-induced cell death in the context of HTLV-1-infected cells. ROS measurements showed an increasing gradient from resting to mitogenactivated primary T cells to transformed T cells (Jurkat). Expression of p13 in primary T cells resulted in their activation, an effect that was abrogated by ROS scavengers. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels; in the context of the HTLV-1 propagation strategy, p13 could increase the pool of "normal" infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host. (Blood. 2010;116(1): 54-62) IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects an estimated 20 million people worldwide. HTLV-1 is the causative agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4ϩ T cells that is refractory to current therapies. ATLL arises in approximately 3% of HTLV-1-infected persons and is preceded by a decades-long clinical latency.Many aspects of HTLV-1 replication, persistence, and pathogenesis remain incompletely understood (reviewed in Verdonck et al 1 ). Studies so far have been focused primarily on the transcriptional activator Tax, which is essential for expression from the viral promoter, and the posttranscriptional factor Rex, which is required for expression of incompletely spliced viral transcripts. Tax also plays a critical role in T-cell transformation through its ability to deregulate the expression of a vast array of cellular genes and interfere with cell-cycle checkpoints, producing major alterations in cell proliferation and survival and promoting genetic instability (reviewed in Lairmore et al 2 ). Indeed, expression of Tax in mouse thymocytes is sufficient for induction of T-cell leukemia/ lymphoma. 3 However, the contrast between the powerful oncogenic properties of Tax and the low prevalence and long latency of ATLL suggests the existence of mechanisms that limit the transforming potential of the virus and favor its lifelong persistence in the host in the absence of disease.Recent studies indicate that the viral accessory proteins p12, p21, p30, HBZ, and p13 may also contribute to HTLV-1 replication and pathogenesis (reviewed in Nicot et al 4 ). The present study is focused on p13, an 87-amino acid accessory prote...