Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer.

Recent studies suggest that Peroxiredoxin 1 (Prdx1), in addition to its known H2O2-scavenging function, mediates cell signaling through redox-specific protein-protein interactions. Our data illustrate how Prdx1 specifically coordinates p38MAPK-induced signaling through regulating p38MAPKα phosphatases in an H2O2 dose-dependent manner. MAPK phosphatases (MKP-1 and/or MKP-5), which are known to dephosphorylate and deactivate the senescence-inducing MAPK p38α, belong to a group of redox-sensitive phosphatases (protein tyrosine phosphatases) characterized by a low pKa cysteine in their active sites. We found that Prdx1 bound to both MKP-1 and MKP-5, but dissociated from MKP-1 when the Prdx1 peroxidatic cysteine Cys52 was over-oxidized to sulfonic acid, which in turn resulted in MKP-1 oxidation-induced oligomerization and inactivity toward p38MAPKα. Conversely, over-oxidation of Prdx1-Cys52 was enhancing in the Prdx1:MKP-5 complex with increasing amounts of H2O2 concentrations and correlated with a protection from oxidation-induced oligomerization and inactivation of MKP-5 so that activation toward p38MAPK was maintained. Further examination of this Prdx1-specific mechanism in a model of reactive oxygen species-induced senescence of human breast epithelial cells revealed the specific activation of MKP-5, resulting in decreased p38MAPKα activity. Taken together, our data suggest that Prdx1 orchestrates redox signaling in an H2O2 dose-dependent manner through the oxidation status of its peroxidatic cysteine Cys52.

[New medical treatments in pituitary adenomas]. / Actualités thérapeutiques dans la prise en charge médicale des adénomes hypophysaires.

Currently, the role of dopaminergic and somatostatinergic agonists in the treatment of pituitary adenomas is quite well established. Nevertheless, a clearer understanding of the expression of dopaminergic and somatostatinergic receptors at the cellular level of pituitary adenomas as well as the development of newer analogues compounds may drastically change current therapeutic modalities. In particular, the emphasis on the co-expression of different receptors types or subtypes in adenomatous cells highlights functional interactions between receptors leading to an increase in their activity. Newer molecules are also in the process of development : new somatostatin analogues with more universal binding properties to different receptors subtypes, as well as chimeric molecules capable of binding to somatostatinergic and dopaminergic receptors. In the midst of GH-secreting pituitary adenomas, a positive correlation exists between the expression of Sst2 mRNA and the inhibition of GH release by somatostatin analogues. The involvement of Sst5 subtype in adenomas resistant to preferential Sst2 agonists has recently been proved. Another recently developed compound has a more universal Sst binding profile. This compound, named SOM-230, has a 25, 5 and 40 times higher binding affinity to Sst1, Sst3 and Sst5 receptors respectively, and 2,5 times lower affinity to Sst2, when compared to octreotide. SOM-230 could therefore allow for much more effective methods in treating patients suffering from acromegaly. Besides, the use of a chimeric molecule presenting a binding affinity to both Sst2 and D2 subtypes (BIM-23A287) inhibits the secretion of GH in ways similar to the Sst2 or D2 agonists used alone or concurrently but however in a concentration 50 times lower than that of the latter. The discovery of Sst5 and D2 subtypes at the level of corticotropic adenomas reveals newer therapeutic perspectives with promising preliminary results with the use of SOM-230 ; these finding lead to a rise in interest in cabergoline. In the midst of non-functioning pituitary adenomas, the expression of Sst2, Sst3 and D2 receptors will perhaps allow the use of combined therapies associating the new somatostatin analogues to the dopaminergic agonists or even use dopastatin (BIM-23A760, chimeric molecule Sst2-Sst5-D2). The preliminary results obtained in vitro with this molecule are actually encouraging since they show a dose dependent inhibition of the cellular replication mechanisms in 60 % of the cases. Finally, concerning prolactinomas the discovery of Sst5 receptors lead to consider the use of somatostatinergic agonists specific to the Sst5 receptor, SOM-230 in particular. Nevertheless, it seems that adenomas resistant to dopaminergic agonist due to a lack of expression of D2 receptor fail to express Sst5 receptors as well. On the other hand, dopastatin appears to be more efficient than cabergoline in the management of this type of adenomas. Therefore, the growing awareness concerning the mechanisms involved in the control of pituitary secretions as well as cellular proliferation will perhaps allow physicians to treat the pathology of pituitary adenomas, macroadenomas in particular, using solely pharmacological means instead of invasive surgical procedures and/or radiotherapy.