Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells.

Inhibition of androgen receptor (AR) signalling represents the conventional medical management of prostate cancer. Ultimately this treatment fails because tumors develop an incurable, castrate resistant phenotype, resulting in an unmet need for new treatments in prostate cancer. The AR remains a viable therapeutic target in castrate resistant disease, such that novel ways of downregulating AR activities are attractive as potential treatments. Here we describe a mechanism by which the AR can be downregulated by the MDM2 antagonist Nutlin-3, resulting in loss of pro-survival c-FLIP gene expression and apoptosis. We additionally show that loss of c-FLIP sensitises prostate cancer cells to Nutlin-3. Finally, we demonstrate that the unrelated MDM2 antagonist Mi-63 also impinges upon AR signalling, supporting the concept of future treatment of prostate cancer with MDM2 antagonists.

KDM4B is a master regulator of the estrogen receptor signalling cascade.

The importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.

p38(MAPK): stress responses from molecular mechanisms to therapeutics.

The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discuss how the p38(MAPK) pathway might be best exploited for the development of more effective therapeutics with minimal side effects in a range of specific disease settings.

The role of humic non-exchangeable binding in the promotion of metal ion transport in groundwaters in the environment.

Metal ions form strong complexes with humic substances. When the metal ion is first complexed by humic material, it is bound in an 'exchangeable' mode. The metal ion in this fraction is strongly bound, however, if the metal-humic complex encounters a stronger binding site on a surface, then the metal ion may dissociate from the humic substance and be immobilised. However, over time, exchangeably-bound metal may transfer to a 'non-exchangeable' mode. Transfer into this mode and dissociation from it are slow, regardless of the strength of the competing sink, and so immobilisation may be hindered. A series of coupled chemical transport calculations has been performed to investigate the likely effects of non-exchangeable binding upon the transport of metal ions in the environment. The calculations show that metal in the non-exchangeable mode will have a significantly higher mobility than that in the exchangeable mode. The critical factor is the ratio of the non-exchangeable first-order dissociation rate constant and the residence time in the groundwater column, metal ion mobility increasing with decreasing rate constant. A second series of calculations has investigated the effect of the sorption to surfaces of humic/metal complexes on the transport of the non-exchangeably bound metal. It was found that such sorption may reduce mobility, depending upon the humic fraction to which the metal ion is bound. For the more weakly sorbing humic fractions, under ambient conditions (humic concentration etc.) the non-exchangeable fraction may still transport significantly. However, for the more strongly sorbed fractions, the non-exchangeable fraction has little effect upon mobility. In addition to direct retardation, sorption also increases the residence time of the non-exchangeable fraction, giving more time for dissociation and immobilisation. The non-exchangeable dissociation reaction, and the sorption reaction have been classified in terms of two Damkohler numbers, which can be used to determine the importance of chemical kinetics during transport calculations. These numbers have been used to develop a set of rules that determine when full chemical kinetic calculations are required for a reliable prediction, and when equilibrium may be assumed, or when the reactions are sufficiently slow that they may be ignored completely.