The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer.

Often described as a mediator of cell cycle arrest or as a pro-apoptotic factor in stressful conditions, the MAP3K ZAK (Sterile alpha motif and leucine zipper-containing kinase) has also been proven to positively regulate epidermal growth factor receptor (EGFR) and WNT signaling pathways, cancer cell proliferation and cellular neoplastic transformation. Here, we show that both isoforms of ZAK, ZAK-α and ZAK-ß are key factors in cancer cell migration. While ZAK depletion reduced cell motility of HeLa and HCT116 cells, its overexpression triggered the activation of all three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, as well as an increase in cell motion. On the contrary, the kinase-dead mutants, ZAK-α K45M and ZAK-ß K45M, were not able to provoke such events, and instead exerted a dominant-negative effect on MAPK activation and cell migration. Pharmacological inhibition of ZAK by nilotinib, preventing ZAK-autophosphorylation and thereby auto-activation, led to the same results. Activated by epidermal growth factor (EGF), we further showed that ZAK constitutes an essential element of the EGF/ERK-dependent cell migration pathway. Using public transcriptomic databases and tissue microarrays, we finally established that, as strong factors of the EGFR signaling pathway, ZAK-α and/or ZAK-ß transcripts and protein(s) are frequently upregulated in colorectal adenoma and carcinoma patients. Notably, gene set enrichment analysis disclosed a significant correlation between ZAK+ colorectal premalignant lesions and gene sets belonging to the MAPK/ERK and motility-related signaling pathways of the reactome database, strongly suggesting that ZAK induces such pro-tumoral reaction cascades in human cancers.

Surface decoration of catanionic vesicles with superparamagnetic iron oxide nanoparticles: a model system for triggered release under moderate temperature conditions.

We report the design of new catanionic vesicles decorated with iron oxide nanoparticles, which could be used as a model system to illustrate controlled delivery of small solutes under mild hyperthermia. Efficient release of fluorescent dye rhodamine 6G was observed when samples were exposed to an oscillating magnetic field. Our system provides direct evidence for reversible permeability upon magnetic stimulation.

NMR-D study of the local spin dynamics and magnetic anisotropy in different nearly monodispersed ferrite nanoparticles.

We present a systematic experimental comparison of the superparamagnetic relaxation time constants obtained by means of dynamic magnetic measurements and (1)H-NMR relaxometry, on ferrite-based nanosystems with different composition, various core sizes and dispersed in different solvents. The application of a heuristic model for the relaxivity allowed a comparison between the reversal time of magnetization as seen by NMR and the results from the AC susceptibility experiments, and an estimation of fundamental microscopic properties. A good agreement between the NMR and AC results was found when fitting the AC data to a Vogel-Fulcher law. Key parameters obtained from the model have been exploited to evaluate the impact of the contribution from magnetic anisotropy to the relaxivity curves and estimate the minimum approach distance of the bulk solvent.

Electrical coupling and plasticity of the mitochondrial network.

Kinetic fluorescence imaging and the potentiometric probe tetramethylrhodamine methyl ester (TMRM) were used to evoke and detect changes in membrane potential (delta Psi(m)) of individual mitochondria in living cells. As a combined effect of preferential TMRM accumulation in mitochondria, and of TMRM photoactivation, individual organelles displayed sharp transient depolarizations caused by local reactive oxygen species (ROS)-mediated gatings of the mitochondrial permeability transition pore (PTP). In COS-7 cells, such directed repetitive gatings of the PTP gave rise to stochastic delta Psi(m)flickering at the level of individual organelles, but also to prominent synchronous delta Psi(m)transitions in whole subgroups of the mitochondrial population, indicative of the existence of an underlying electrically coupled mitochondrial network. In single cells, this network could comprise as much as 65% of the total mitochondrial population, a nd exhibited a high plasticity with mitochondrial units spontaneously connecting to and disconnecting from the coupled structure within seconds. These results indicate that in resting cells, the mitochondrial network is a dynamic proton-conducting structure capable to commute and coordinate electrical signals generated by the PTP.