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The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide ([H.sub.2][O.sub.2]), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-κB, p53, and HIF-1α, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets- 1, a factor that has been increasingly associated with aggressive cancers. Key words: mitochondria, reactive oxygen species, cancer, nuclear crosstalk, transcription factors, hypoxia, mitochondrial signaling, ETS. Les mitochondries sont des organites cellulaires uniques qui contiennent leur propre genome et, conjointement avec le noyau, sont capables de transcrire et de traduire les genes codant pour les constituants de la chaine de transport des electrons (CTE). Pour ce faire, les mitochondries doivent communiquer avec le noyau par la production d'especes reactives de l'oxygene (ROS), comme le peroxyde d'hydrogene ([H.sub.2][O.sub.2]), qui sont generees par un sous-produit de la respiration aerobie a l'interieur des mitochondries. On postule que la signalisation mitochondriale est alteree dans les cellules cancereuses, oil l'on observe frequemment des mutations dans le genome mitochondrial et des modifications dans les caracteristiques fonctionnelles des mitochondries causant une augmentation de la glycolyse. En tant que molecules de signalisation, les ROS oxydent et inhibent les MAPK phosphatases, ce qui provoque une augmentation de la proliferation et de la survie, un effet particulierement avantageux pour les cellules cancereuses. En matiere de regulation transcriptionnelle, les ROS influent sur la phosphorylation, l'activation, l'oxydation, et la liaison de l'ADN de facteurs de transcription tels que AP-1, NF-κB, p53 et HIF-1α, entrainant des modifications dans l'expression de genes cibles. L'augmentation de la production de ROS par les mitochondries defectueuses des cellules cancereuses va aussi causer une activation du facteur de transcription Ets-1, un facteur de plus en plus associe aux cancers agressifs. Mots-cles: mitochondries, especes reactives de l'oxygene, cancer, dialogue (crosstalk) nucleaire, facteurs de transcription, hypoxie, signalisation mitochondriale, ETS. [Traduit par la Redaction], Introduction Several important functional changes to cancer cell mitochondria have been observed that implicate this organelle in tumor formation, including the increased production of reactive oxygen species (ROS), decreased oxidative [...]

Despite huge economic and intellectual investments, developing effective cancer treatments continues to be an overarching challenge. Engineered oncolytic viruses (OVs) present self-amplifying immunotherapy platforms capable of preferential cytotoxicity to cancer cells and simultaneous activation of host anti-tumor immunity. In preclinical studies, OVs are showing potent therapeutic effects when used in combination with other immune therapy strategies. In the clinic, the immunotherapeutic effects of OVs are showing promising results. Here we review current strategies for engineering OVs, and present a perspective of future directions within a discussion of the current outcomes of combinatorial approaches with other cancer immunotherapy platforms. [ABSTRACT FROM AUTHOR]

Background Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance. Many chemotherapeutic agents rely on the induction of oxidative stress to cause cancer cell death, thus targeting redox regulation is a promising strategy to overcome drug resistance. Methods We have used a tetracycline-inducible Ets-1 overexpression model derived from 2008 ovarian cancer cells in the present study. To examine the role of Ets-1 in glutathione regulation we have measured intracellular reactive oxygen species and glutathione levels, as well as glutathione peroxidase enzyme activity. Glutathione synthesis was limited using transsulfuration or Sxc - pathway blocking agents, and glutamate release was measured to confirm Sxc - blockade. Cell viability following drug treatment was assessed via crystal violet assay. Oxidative stress was induced through glucose oxidase treatment, which produces hydrogen peroxide by glucose oxidation. The protein expressions of redox-related factors were measured through western blotting. Results Overexpression of Ets-1 was associated with decreased intracellular ROS, concomitantly with increased intracellular GSH, GPX antioxidant activity, and Sxc - transporter activity. Under basal conditions, inhibition of the transsulfuration pathway resulted in decreased GSH levels and GPX activity in all cell lines, whereas inhibition of Sxc - by sulfasalazine decreased GPX activity in Ets-1-expressing cells only. However, under oxidative stress the intracellular GSH levels decreased significantly in correlation with increased Ets-1 expression following sulfasalazine treatment. Conclusions In this study we have identified a role for proto-oncogene Ets-1 in the regulation of intracellular glutathione levels, and examined the effects of the anti-inflammatory drug sulfasalazine on glutathione depletion using an ovarian cancer cell model. The findings from this study show that Ets-1 mediates enhanced Sxc - activity to increase glutathione levels under oxidative stress, suggesting that Ets-1 could be a promising putative target to enhance conventional therapeutic strategies. [ABSTRACT FROM AUTHOR]

Cancer cells predominantly utilize glycolysis for ATP production even in the presence of abundant oxygen, an environment that would normally result in energy production through oxidative phosphorylation. Although the molecular mechanism for this metabolic switch to aerobic glycolysis has not been fully elucidated, it is likely that mitochondrial damage to the electron transport chain and the resulting increased production of reactive oxygen species are significant driving forces. In this study, we have investigated the role of the transcription factor Ets-1 in the regulation of mitochondrial function and metabolism. Ets-1 was over-expressed using a stably-incorporated tetracycline-inducible expression vector in the ovarian cancer cell line 2008, which does not express detectable basal levels of Ets-1 protein. Microarray analysis of the effects of Ets-1 over-expression in these ovarian cancer cells shows that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. In contrast, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. At the functional level, we have found that Ets-1 expression is directly correlated with cellular oxygen consumption whereby increased expression causes decreased oxygen consumption. Ets-1 over-expression also caused increased sensitivity to glycolytic inhibitors, as well as growth inhibition in a glucose-depleted culture environment. Collectively our findings demonstrate that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in ovarian cancer cells. [ABSTRACT FROM AUTHOR]