title: Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics.
abstract: The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change ≥2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC.
authors: King Fahd Medical Research Center, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Zeenat
authors: Z
authors: Mirza
authors: Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Hans-Juergen
authors: HJ
authors: Schulten
authors: Department of Urology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors: Hasan Ma
authors: HM
authors: Farsi
authors: Department of Pathology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia; Department of Pathology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
authors: Jaudah A
authors: JA
authors: Al-Maghrabi
authors: Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Mamdooh A
authors: MA
authors: Gari
authors: King Fahd Medical Research Center, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia; Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Adeel Ga
authors: AG
authors: Chaudhary
authors: King Fahd Medical Research Center, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia; Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia; KACST Technology Innovation Center in Personalized Medicine at King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Adel M
authors: AM
authors: Abuzenadah
authors: Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Mohammed H
authors: MH
authors: Al-Qahtani
authors: Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.
authors: Sajjad
authors: S
authors: Karim
mesh_terms: D040501:Calgranulin A / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D040501:Calgranulin A; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D019311:Staurosporine; C059539:midostaurin