AbstractBackground: Despite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumour, underlying the need of novel strategies that can target the complexities of this disease and bypass the development of drug-resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of the antiepileptic with histone deacetylase inhibitory activity valproic acid (VPA), and the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment, both in vitro and in vivo models, by targeting cancer stem cells compartment via mevalonate pathway/YAP axis modulation. Methods Here, by a combined proteomic and metabolomic/lipidomic approach we characterized tumor samples derived from 22Rv1 mCRPC cells xenografted mice, treated or not with VPA/SIM combination, coupled with an in deep bioinformatics analysis. Results We confirmed a specific impact of VPA/SIM on Hippo-YAP signaling pathway, functionally related with modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the VPA/SIM antitumor effect. Conclusions In the current study, we present an in-depth exploration of the potential to repurpose in mCRPC treatment two generic and safe drugs, valproic acid (VPA) and simvastatin (SIM), that already showcased anti-tumor efficacy in combination, primarily affecting cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of LC-MS/MS proteomics and of 1H-NMR metabolomics/lipidomics results, confirmed a specific impact of VPA/SIM on Hippo-YAP
WSCI (Wheat Subtilisin/Chymotrypsin Inhibitor) is a small protein belonging to the Potato inhibitor I family exhibiting a high content of essential amino acid. In addition to bacterial subtilisins and mammalian chymotrypsins, WSCI inhibits chymotrypsin-like activities isolated from digestive traits of a number of insect larvae. In vivo, as suggested for many plant proteinase inhibitors, WSCI seems to play a role of natural defence against attacks of pests and pathogens. The functional region of WSCI, containing the inhibitor reactive site (Met48-Glu49), corresponds to an extended flexible loop (Val42-Asp53) whose architecture is somehow stabilized by a number of secondary interactions established with a small β-sheet located underneath. The aim of this study was to employ a WSCI molecule as a stable scaffold to obtain recombinant inhibitors with new acquired anti-proteinase activity or, alternatively, inactive WSCI variants. A gene sequence coding for the native WSCI, along with genes coding for muteins with different specficities, could be exploited to obtain transformed non-food use plants with improved insect resistance. On the other hand, the genetic transformation of cereal plants over-expressing inactive WSCI muteins could represent a possible strategy to improve the nutritional quality of cereal-based foods, without risk of interference with human or animal digestive enzymes. Here, we described the characterization of four muteins containing single/multiple amino acid substitutions at the WSCI reactive site and/or at its proximity. Modalities of interaction of these muteins with proteinases (subtilisin, trypsin and chymotrypsin) were investigated by time course hydrolysis and molecular simulations studies.
Human circadian rhythms connect internal biological clock and external environmental through earth’s day and night alternating. The human circadian clocks, present in each organs, are controlled by a main pace-maker situated in SCN (suprachiasmatic nuclei) of hypothalamus which is synchronized to the daily photoperiod. Clock disturbances are involved in many diseases like diabetes, obesity, depression, bipolar disease, and many types of cancers like breast cancer, colon cancer as well as hepatocellular carcinoma which is the third most life claiming cancer around the world. In this work the protein- protein interaction networks were analyzed using Cytoscape software. The human circadian network consists of 2151 nodes and 75821 interactions making it a huge network. It is very centralized with the value of 0.235. The density of the network is 0.033 and heterogeneity of 1.012. The characteristic path length is 2.373 while the average number of neighbors is equal to 70.5. Recently we performed a network analysis on gene expression data obtained in our group from HepG2 cells, a liver cancer cell line that lacks the viral infection, identifying 26 HUB genes [1]. Among these genes, 20 of them resulted present in the human circadian rhythm network. All these 20 genes had high degree values in the circadian network, ranging from 287 to 77 indicating that they control a large number of functional interactions and the information flow through the circadian network. However, by merging the network of genes involved in human circadian rhythms as well HepG2, we found that 83 hub nodes are common. This establishes strong relationships between liver cancer and circadian rhythms.
In metastatic colorectal cancer (mCRC) patients (pts), treatment strategies integrating liver resection with induction chemotherapy offer better 5-year survival rates than chemotherapy alone. However, liver resection is a complex and costly procedure, and recurrence occurs in almost 2/3rds of pts, suggesting the need to identify those at higher risk. The aim of this work was to evaluate whether the integration of plasma metabolomics and lipidomics combined with the multiplex analysis of a large panel of plasma cytokines can be used to predict the risk of relapse and other patient outcomes after liver surgery, beyond or in combination with clinical morphovolumetric criteria.Peripheral blood metabolomics and lipidomics were performed by 600 MHz NMR spectroscopy on plasma from 30 unresectable mCRC pts treated with bevacizumab plus oxaliplatin-based regimens within the Obelics trial (NCT01718873) and subdivided into responder (R) and non-R (NR) according to 1-year disease-free survival (DFS): ≥ 1-year (R, n = 12) and < 1-year (NR, n = 18). A large panel of cytokines, chemokines, and growth factors was evaluated on the same plasma using Luminex xMAP-based multiplex bead-based immunoassay technology. A multiple biomarkers model was built using a support vector machine (SVM) classifier.Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing metabolomics profiles of samples collected at the time of response evaluation when resectability was established showed significantly different levels of metabolites between the two groups. Two metabolites, 3-hydroxybutyrate and histidine, significantly predicted DFS and overall survival. Lipidomics analysis confirmed clear differences between the R and NR pts, indicating a statistically significant increase in lipids (cholesterol, triglycerides and phospholipids) in NR pts, reflecting a nonspecific inflammatory response. Indeed, a significant increase in proinflammatory cytokines was demonstrated in NR pts plasma. Finally, a multiple biomarkers model based on the combination of presurgery plasma levels of 3-hydroxybutyrate, cholesterol, phospholipids, triglycerides and IL-6 was able to correctly classify patients by their DFS with good accuracy.Overall, this exploratory study suggests the potential of these combined biomarker approaches to predict outcomes in mCRC patients who are candidates for liver metastasis resection after induction treatment for defining personalized management and treatment strategies.
Several studies have highlighted the key role of chronic inflammation in breast cancer development, progression, metastasis, and therapeutic outcome. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation. Recent findings suggest that positive psychosocial experiences, including psychotherapeutic interventions and therapeutic mind-body protocols, can modulate the inflammatory response by reducing the expression of genes/proteins associated with inflammation and stress-related pathways. Our preliminary results indicate that a specific mind-body therapy (MBT-T) could induce a significant reduction of the release of different cytokines and chemokines, such as SCGFβ, SDF-1α, MCP3, GROα, LIF, and IL-18, in the sera of breast cancer patients compared to a control group, suggesting that MBT-T could represent a promising approach to improve the wellness and outcome of breast cancer patients.
Marine organisms possess a series of cellular strategies to counteract the negative effects of toxic compounds, including the massive reorganization of gene expression networks. Here we report the modulated dose-dependent response of activated genes by diatom polyunsaturated aldehydes (PUAs) in the sea urchin Paracentrotus lividus. PUAs are secondary metabolites deriving from the oxidation of fatty acids, inducing deleterious effects on the reproduction and development of planktonic and benthic organisms that feed on these unicellular algae and with anti-cancer activity. Our previous results showed that PUAs target several genes, implicated in different functional processes in this sea urchin. Using interactomic Ingenuity Pathway Analysis we now show that the genes targeted by PUAs are correlated with four HUB genes, NF-κB, p53, δ-2-catenin and HIF1A, which have not been previously reported for P. lividus. We propose a working model describing hypothetical pathways potentially involved in toxic aldehyde stress response in sea urchins. This represents the first report on gene networks affected by PUAs, opening new perspectives in understanding the cellular mechanisms underlying the response of benthic organisms to diatom exposure.
