Apigenin exerts anti-cancer effects in colon cancer by targeting HSP90AA1.

Apigenin, a flavonoid, has shown early promise in colon cancer (CC); thus, exploring potential mechanisms of Apigenin is obligatory. In this study, shared targets of Apigenin and CC were identified through online tools, which were then subjected to functional enrichment analyses, Gene Ontology and KEGG. Further, the protein-protein interaction network of the shared targets was developed (via STRING). The top targets of Apigenin in CC were identified by molecular docking; further investigated for differential gene and protein expression in CC and their influence on CC patient survival (using TCGA data). Out of 13 hub genes, the top 3 targets (HSP90AA1, MMP9, PTGS2) were selected based on docking score. Their expression was significantly elevated and related to poor overall survival in CC (except PTGS2). Molecular dynamics simulation further validated protein-ligand interactions and divulged HSP90AA1 as the best target of Apigenin in CC. Finally, the anti-cancer effects of Apigenin and its major metabolite, luteolin, were investigated in CC, which is involved in the cytotoxicity of CC cells (COLO-205) by reducing HSP90AA1 expression revealed by real-time PCR. Thus, HSP90AA1 was identified as one of the prime targets of Apigenin in CC, and Apigenin could be effective against CC.Communicated by Ramaswamy H. Sarma.

Targeting UNC-51-like kinase 1 and 2 by lignans to modulate autophagy: possible implications in metastatic colorectal cancer.

Colorectal cancer (CRC), especially metastatic (mCRC) form, becomes a major reason behind cancer morbidity worldwide, whereas the treatment strategy is not optimum. Several novel targets are under investigation for mCRC including the autophagy pathway. Natural compounds including dietary lignans are sparsely reported as autophagy modulators. Nonetheless, the interaction between dietary lignans and core autophagy complexes are yet to be characterised. We aimed to describe the interaction between the dietary lignans from flaxseed (Linum usitatissimum) and sesame seeds (Sesamum indicum) along with the enterolignans (enterodiol and enterolactone) and the UNC-51-like kinase 1 and 2 (ULK1/2), important kinases required for the autophagy. A range of in-silico technologies viz. molecular docking, drug likeness, and ADME/T was employed to select the best fit modulator and/or inhibitor of the target kinases from the list of selected lignans. Drug likeness and ADME/T studied further selected the best-suited lignans as potential autophagy inhibitor. Molecular dynamic simulation (MDS) analyses were used to validate the molecular docking results. Binding free energies of the protein-ligand interactions by MM-PBSA method further confirmed best-selected lignans as ULK1 and/or ULK2 inhibitor. In conclusion, three dietary lignans pinoresinol, medioresinol, and lariciresinol successfully identified as dual ULK1/2 inhibitor/modifier, whereas enterodiol emerged as a selective ULK2 inhibitor/modifier.

Targeting protein tyrosine phosphatase 1B in obesity-associated colon cancer: Possible role of sweet potato (Ipomoea batatas).

Protein tyrosine phosphatase 1B (PTP1B) has emerged as one of the links between obesity and colon cancer (CC). Anti-obesity and anti-CC attributes of sweet potato (Ipomoea batatas) reported sparsely. Here, we aimed to study the potential of PTP1B as a target in CC, particularly in obese population. Expression and genomic alteration frequency of PTPN1 (PTP1B) were checked in CC. Interacting partners of PTP1B through STRING and hub genes through Cytoscape (MCODE) were identified. Hub genes were subjected to functional enrichment analyses (via Metascape), differential gene expression, copy number variation, and single nucleotide variation analyses (GSCA database). Cancer-related pathways and associated immune infiltrates of the hub genes were checked too. Eleven sweet potato-derived compounds selected through drug likeness (DL) and toxicity filters were explored via molecular docking (AutoDock Vina) to reveal the interactions with PTP1B. Genomic alteration frequency of the PTPN1 was highest in CC compared to all the other TCGA cancers, and a high expression (RNA and protein) is also observed in CC that correlated well to a poor overall survival (OS). Furthermore, PTP1B and related proteins were enriched in different biological processes and signaling pathways related to carcinogenesis including epithelial-mesenchymal transition. Overall, PTP1B identified as a potential target in obesity-linked CC and sweet potato might exert its protective action by targeting the PTP1B. Sweet potato compounds (e.g., pelargonidin and luteolin) interacted with the catalytic P loop and the WPD loop of the PTP1B. Furthermore, MD simulation study ascertained that luteolin has the highest affinity against the PTP1B, whereas pelargonidin and quercetin showed good binding affinity too, thus can be explored further.

Designing of RNA aptamer against DNA binding domain of the glucocorticoid receptor: A response element-based in-silico approach.

Virtual screening, a conventional in-silico approach to design an RNA aptamer against target proteins require huge RNA library containing 1010 to 1015 combination of RNA oligomers and high-performance computing systems. However, in the case of nuclear receptor proteins, screening can be narrowed down by using response element sequences rather than random RNA oligomer library. In this study, we used a novel method to design RNA aptamer against the DNA binding domain of the glucocorticoid receptor α (GRα). GRα plays a vital role in cancer metastasis such as colon, cervical and breast cancer by activating the S100A8 calcium-binding protein, which makes it a potential drug target for those cancers. We started the screening of 24 RNA aptamers (16 nucleotides long), all of which are glucocorticoid response elements (GRE) of S100A8. Among the aptamers screened, Apt-2, Apt-5, Apt-6 and Apt-15 are found to be most suitable by molecular docking and dynamic studies. The stability and compactness of the aptamer-protein complexes were assessed by GROMACS. The binding energies were rescored using the MM-PBSA method, which were -3679.581, -3690.892, -8246.052 and -3412.802 KJ/mol, respectively for Apt-2, Apt- 5, Apt-6 and Apt-15. The designed RNA aptamer may directly bind to the DNA binding domain of GR and prevent the trans-activation of the S100A8 gene by blocking the binding of GR to its response element. Thus, this novel approach of design the response elements-based RNA aptamer against GRα like nuclear receptor proteins will help to generate target-specific RNA aptamers with minimal efforts and cost.Communicated by Ramaswamy H. Sarma.

Potential of olive oil and its phenolic compounds as therapeutic intervention against colorectal cancer: a comprehensive review.

Colorectal cancer (CRC) is one of the major causes of death across the world and incidence rate of CRC increasing alarmingly each passing year. Diet, genomic anomalies, inflammation and deregulated signalling pathways are among the major causes of CRC. Because of numerous side effects of CRC therapies available now, researchers all over the world looking for alternative treatment/preventive strategy with lesser/no side effects. Olive oil which is part of Mediterranean diet contains numerous phenolic compounds that fight against free radicals and inflammation and also well-known for protective role against CRC. The current review focused on the recent evidences where olive oil and its phenolic compounds such as hydroxytyrosol, oleuropein and oleocanthal showed activities against CRC as well to analyse the cellular and molecular signalling mechanism through which these compounds act on. These compounds shown to combat CRC by reducing proliferation, migration, invasion and angiogenesis through regulation of numerous signalling pathways including MAPK pathway, PI3K-Akt pathway and Wnt/ß-catenin pathway and at the same time, induce apoptosis in different CRC model. However, further research is an absolute necessity to establish these compounds as nutritional supplements and develop therapeutic strategy in CRC.

In silico approach to target PI3K/Akt/mTOR axis by selected Olea europaea phenols in PIK3CA mutant colorectal cancer.

Worldwide disease burden of colorectal cancer (CRC) increasing alarmingly, but a suitable therapeutic strategy is not available yet. Abnormal activation of the PI3K/Akt/mTOR signalling because of mutation in the PIK3CA gene is a driving force behind CRC development. Therefore, this study aimed to comprehensively characterise the potential of phenolic compounds from Olea europaea against the PI3K/Akt/mTOR axis by using in silico methodologies. Molecular docking was utilised to study key interactions between phenolic compounds of O. europaea and target proteins PI3K, Akt, mTOR with reference to known inhibitor of target. Drug likeness and ADME/T properties of selected phenols were explored by online tools. Dynamic properties and binding free energy of target-ligand interactions were studied by molecular dynamic simulation and MM-PBSA method respectively. Molecular docking revealed apigenin, luteolin, pinoresinol, oleuropein, and oleuropein aglycone as the top five phenolic compounds which showed comparable/better binding affinity than the known inhibitor of the respective target protein. Drug likeness and ADME/T properties were employed to select the top three phenols namely, apigenin, luteolin, and pinoresinol which shown to bind stably to the catalytic cleft of target proteins as confirmed by molecular dynamics simulations. Therefore, Apigenin, luteolin, and pinoresinol have the potential to be used as the non-toxic alternative to synthetic chemical inhibitors generally used in CRC treatment as they can target PI3K/Akt/mTOR axis. Particularly, pinoresinol showed great potential as dual PI3K/mTOR inhibitor. However, this study needs to be complemented with future in vitro and in vivo studies to provide an alternative way of CRC treatment. Communicated by Ramaswamy H. Sarma.

Wnt5a-Rac1-NF-κB homeostatic circuitry sustains innate immune functions in macrophages.

Macrophages play a critical role in innate immunity. Differentiation Ags present on macrophages such as CD14 orchestrate the first line of defense against infection. The basal/homeostatic signaling scheme that keeps macrophages thus groomed for innate immune functions remains unresolved. Wnt5a-Fz5 signaling being a primordial event during cell differentiation, we examined the involvement of Wnt5a-Fz5 signaling in the maintenance of innate immune functions. In this study, we demonstrate that innate immune functions of macrophages ensue at least partly through a homeostatic Wnt5a-Fz5-NF-κB (p65) circuit, which is Rac1 dependent. The autocrine/paracrine Wnt5a-Fz5-Rac1-p65 signaling cascade not only maintains basal levels of the immune defense modulating IFNs and CD14; it also supports macrophage survival. Wnt5a-Fz5-Rac1 signaling mediated p65 homeostasis in turn sustains Wnt5a expression in a feed-forward mode. The natural immune response of macrophages to Escherichia coli/LPS and virus is accordingly sustained. The depiction of sustenance of innate immune functions as an outcome of a homeostatic Wnt5a-p65 axis unfolds previously unidentified details of immune regulation and provides new insight into homeostatic cell signaling.

The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing.

Phagocytosis is a primary defense program orchestrated by monocytes/macrophages. Unregulated phagocytosis can lead to pathological conditions. In the current study we have demonstrated that Wnt5a stimulates phagocytosis through PI3 kinase-Rac1 and lipid-raft-dependent processes. Wnt5a-mediated augmentation in phagocytosis is suppressed by blocking expression of the putative Wnt5a receptor Frizzled 5. Enhanced phagocytosis of bacteria by Wnt5a-Fz5 signaling increases the secretion of proinflammatory cytokines, but not the bacterial killing rate. Furthermore, a small molecule inhibitor of Wnt production, IWP-2, which reduces secretion of functionally active Wnt5a, not only suppresses both phagocytosis and the secretion of proinflammatory cytokines but also accelerates the bacterial killing rate.