Novel pro-apoptotic, homo- and heterodimeric Smac mimetics/IAPs inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo5.3.0decane scaffold were prepared from monomeric structures ...connected through a head–head (8), tail–tail (9) or head–tail (10) linker. The selection of appropriate decorating functions for the scaffolds, and of rigid and flexible linkers connecting them, is described. The synthesis, purification and analytical characterization of each prepared dimer 8–10 is thoroughly described.
Abstract Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase ...believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members. In epithelial cells, LMTK2 targeting causes the down-regulation of the BCL2 and BCL-xL anti-apoptotic proteins and the reciprocal up-regulation of the pro-apoptotic protein BIM, while, in cancer cells, LMTK2 knock-down reduces BCL2 without increasing BIM levels. We provide evidence that both BIM and BCL2 proteins are regulated by LMTK2 in a GSK3β- and PP1A-dependent manner and that their perturbation, together with BCL-xL reduction, determines an increased sensitivity not only to TRAIL, but also to other compounds. Overall, our findings suggest a broad function of LMTK2 in the regulation of the apoptotic pathway and highlight LMTK2 as a novel candidate target to increase the cytotoxic activity of chemotherapeutic compounds.
Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent ...potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.
Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer ...cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.
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•mTRAIL-R promotes KRAS-driven lung and pancreatic cancer growth and metastasis•Human TRAIL-R2 promotes tumor growth, migration, invasion, and metastasis•Endogenous mTRAIL-R constitutively activates Rac1 in vivo in tumors•TRAIL-R2 expression positively correlates with the onset of metastasis in patients
von Karstedt et al. show that mouse TRAIL-R and human TRAIL-R2, but not TRAIL-R1, are important for the progression, invasion, and metastasis of KRAS-mutant tumors through the regulation of Rac-1.
The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated ...biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.
KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the ...trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation.
An exhaustive comparison among different spatial interpolation algorithms was carried out in order to derive annual and monthly air temperature maps for Sicily (Italy). Deterministic, data-driven and ...geostatistics algorithms were used, in some cases adding the elevation information and other physiographic variables to improve the performance of interpolation techniques and the reconstruction of the air temperature field. The dataset is given by air temperature data coming from 84 stations spread around the island of Sicily. The interpolation algorithms were optimized by using a subset of the available dataset, while the remaining subset was used to validate the results in terms of the accuracy and bias of the estimates. Validation results indicate that univariate methods, which neglect the information from physiographic variables, significantly entail the largest errors, while performances improve when such parameters are taken into account. The best results at the annual scale have been obtained using the the ordinary kriging of residuals from linear regression and from the artificial neural network algorithm, while, at the monthly scale, a Fourier-series algorithm has been used to downscale mean annual temperature to reproduce monthly values in the annual cycle.
Pareidolia refers to the perception of ambiguous sensory patterns as carrying a specific meaning. In its most common form, pareidolia involves human-like facial features, where random objects or ...patterns are illusionary recognized as faces. The current study investigated the neurophysiological correlates of face pareidolia via transcranial alternating current stimulation (tACS). tACS was delivered at gamma (40 Hz) frequency over critical nodes of the "face perception" network (i.e., right lateral occipito-temporal and left prefrontal cortex) of 75 healthy participants while completing four face perception tasks ('Mooney test' for faces, 'Toast test', 'Noise pareidolia test', 'Pareidolia task') and an object perception task ('Mooney test' for objects). In this single-blind, sham-controlled between-subjects study, participants received 35 min of either Sham, Online, (40Hz-tACS_ON), or Offline (40Hz-tACS_PRE) stimulation. Results showed that face pareidolia was causally enhanced by 40Hz-tACS_PRE in the Mooney test for faces in which, as compared to sham, participants more often misperceived scrambled stimuli as faces. In addition, as compared to sham, participants receiving 40Hz-tACS_PRE showed similar reaction times (RTs) when perceiving illusory faces and correctly recognizing noise stimuli in the Toast test, thus not exhibiting hesitancy in identifying faces where there were none. Also, 40Hz-tACS_ON induced slower rejections of face pareidolia responses in the Noise pareidolia test. The current study indicates that 40 Hz tACS can enhance pareidolic illusions in healthy individuals and, thus, that high frequency (i.e., gamma band) oscillations are critical in forming coherent and meaningful visual perception.
A very simple procedure for fabricating inkjet‐printed organic field effect transistors (OFETs) is reported. A reliable process for the deposition of a thin and uniform polymeric dielectric film of ...poly(4‐vinylphenol) (PVP) is established as a key factor for obtaining high performance devices operating at low voltages. To this aim, ink formulations, printing parameters, and cross‐linking processes are investigated. Morphological characterization of the fabricated films by means of contact profilometry and atomic force microscopy is provided, as well as capacitive measurements proving ideal dielectric properties. OFET structures based on PVP gate dielectric are reported: in particular, inkjet‐printed devices operated at voltages below 1 V with remarkable transistor performances such as high charge carrier mobility and low subthreshold swing are presented.
Ultralow voltage (less than 1 V), high mobility (up to 1 cm2 V−1 s−1) inkjet‐printed organic field effect transistors are presented. Low surface trap concentration and a low leakage current (in the range of 10 pA) demonstrate the significant properties of the thin poly(4‐vinylphenol) printed films as gate dielectric layer.
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