Targeting key signalling pathways in oesophageal adenocarcinoma:A reality for personalised medicine?

Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence.We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways.There are many trials underway with the aim of improving survival in oesophageal cancer.Currently,phase 2 and 3 trials are focused on MAP kinase inhibition,either through inhibition of growth factor receptors or signal transducer proteins.In order to avoid tumor resistance,it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas.This may be achievable in the future with the advent of gene signatures and a combinatorial approach.

Herbicide 2,4-dichlorophenoxyacetic acid interferes with MAP kinase signaling in Fusarium graminearum and is inhibitory to fungal growth and pathogenesis

Plant hormones are important for regulating growth,development,and plant-pathogen interactions.Some of them are inhibitory to growth of fungal pathogens but the underlying mechanism is not clear.In this study,we found that hyphal growth of Fusarium graminearum was significantly reduced by high concentrations of IAA and its metabolically stable analogue 2,4-dichlorophenoxyacetic acid(2,4-D).Besides inhibitory effects on growth rate,treatments with 2,4-D also caused significant reduction in conidiation,conidium germination,and germ tube growth.Treatments with 2,4-D had no obvious effect on sexual reproduction but significantly reduced TRI gene expression,toxisome formation,and DON production.More importantly,treatments with 2,4-D were inhibitory to infection structure formation and pathogenesis at concentrations higher than 100μM.The presence of 1000μM 2,4-D almost completely inhibited plant infection and invasive growth.In F.graminearum,2,4-D induced ROS accumulation and FgHog1 activation but reduced the phosphorylation level of Gpmk1 MAP kinase.Metabolomics analysis showed that the accumulation of a number of metabolites such as glycerol and arabitol was increased by 2,4-D treatment in the wild type but not in the Fghog1 mutant.Transformants expressing the dominant active FgPBS2^(S451D T455D) allele were less sensitive to 2,4-D and had elevated levels of intracellular glycerol and arabitol induced by 2,4-D in PH-1.Taken together,our results showed that treatments with 2,4-D interfere with two important MAP kinase pathways and are inhibitory to hyphal growth,DON biosynthesis,and plant infection in F.graminearum.

Dehydroepiandrosterone indirectly inhibits human osteoclastic resorption via activating osteoblastic viability by the MAPK pathway

Background Dehydroepiandrosterone （DHEA） is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the activation of mitogen-activated protein kinase signal pathways during DHEA treatment and the indirect role of osteoblasts （OBs） on osteoclasts under the DHEA treatment of postmenopausal osteoporosis. Methods Primary human OBs and osteoclast-like cells were cultured and, we pretreated OBs with or without U0126 （a highly selective inhibitor of both MEK1 and MEK2）. The OBs were treated with DHEA. We then tested the effects of DHEA on human osteoblastic viability, osteoprotegerin production and the expression of phosphor-ERK1/2 （extracellular signal-regulated kinase）. In the presence or absence of OBs, the function of osteoclastic resorption upon DHEA treatment was calculated. Results DHEA promoted the human osteoblastic proliferation and inhibited the osteoblastic apoptosis within the concentration range of 108-106 mol/L （P 〈0.05, P 〈0.01, respectively）. Within the effective concentration range, the expression of phosphor-ERK1/2 and osteoprotegerin was increased by DHEA and blocked by U0126. In the presence of OBs, DHEA could significantly decrease the number and the area of bone resorption lacuna （P 〈0.05 and P 〈0.01, respectively）. Without OBs, however, the effects of DHEA on the bone resorption lacuna were almost completely abolished. Conclusions DHEA could indirectly inhibit the human osteoclastic resorption through promoting the osteoblastic viability and osteoprotegerin production, which is mediated by mitogen-activated protein kinases signal pathway involving the phosphor-ERK1/2.