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Impact of S100A8 Expression on Kidney Cancer Progression and Molecular Docking Studies for Kidney Cancer Therapeutics

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Impact of S100A8 Expression on Kidney Cancer Progression and Molecular Docking Studies for Kidney Cancer Therapeutics ANTICANCER RESEARCH 34: 1873-1884 (2014) Impact of S100A8 Expression on Kidney Cancer Progression and Molecular Docking Studies for Kidney Cancer Therapeutics ZEENAT MIRZA1, HANS-JUERGEN SCHULTEN2, HASAN MA FARSI3, JAUDAH A. AL-MAGHRABI4,5, MAMDOOH A. GARI2, ADEEL GA CHAUDHARY1,2, ADEL M. ABUZENADAH1,2, MOHAMMED H. AL-QAHTANI2 and SAJJAD KARIM2 1King Fahd Medical Research Center, and 2Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Urology, and 4Department of Pathology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia; 5Department of Pathology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia Abstract. Background/Aim: The proinflammatory protein calculations. Detailed analysis of bound structures and their S100A8, which is expressed in myeloid cells under physiological binding free energies was carried out for S100A8, its known conditions, is strongly expressed in human cancer tissues. Its partner (S100A9), and S100A8−S100A9 complex (calprotectin). role in tumor cell differentiation and tumor progression is Results: In our microarray experiments, we identified 1,335 largely unclear and virtually unstudied in kidney cancer. In the significantly differentially expressed genes, including S100A8, present study, we investigated whether S100A8 could be a in kidney cancer using a cut-off of p<0.05 and fold-change of 2. potential anticancer drug target and therapeutic biomarker for Functional analysis of kidney cancer-associated genes showed kidney cancer, and the underlying molecular mechanisms by overexpression of genes involved in cell-cycle progression, exploiting its interaction profile with drugs. Materials and DNA repair, cell death, tumor morphology and tissue Methods: Microarray-based transcriptomics experiments using development. Pathway analysis showed significant disruption Affymetrix HuGene 1.0 ST arrays were applied to renal cell of pathways of atherosclerosis signaling, liver X carcinoma specimens from Saudi patients for identification of receptor/retinoid X receptor (LXR/RXR) activation, notch significant genes associated with kidney cancer. In addition, we signaling, and interleukin-12 (IL-12) signaling. We identified retrieved selected expression data from the National Center for S100A8 as a prospective biomarker for kidney cancer and in Biotechnology Information Gene Expression Omnibus database silico analysis showed that aspirin, celecoxib, dexamethasone for comparative analysis and confirmation of S100A8 and diclofenac binds to S100A8 and may inhibit downstream expression. Ingenuity Pathway Analysis (IPA) was used to signaling in kidney cancer. Conclusion: The present study elucidate significant molecular networks and pathways provides an initial overview of differentially expressed genes in associated with kidney cancer. The probable polar and non- kidney cancer of Saudi Arabian patients using whole-transcript, polar interactions of possible S100A8 inhibitors (aspirin, high-density expression arrays. Our analysis suggests distinct celecoxib, dexamethasone and diclofenac) were examined by transcriptomic signatures, with significantly high levels of performing molecular docking and binding free energy S100A8, and underlying molecular mechanisms contributing to kidney cancer progression. Our docking-based findings shed insight into S100A8 protein as an attractive anticancer target Correspondence to: Dr. Sajjad Karim, Center of Excellence in for therapeutic intervention in kidney cancer. To our knowledge, Genomic Medicine Research, King Abdulaziz University, PO BOX this is the first structure-based docking study for the selected 80216, Jeddah 21589, Kingdom of Saudi Arabia. Tel: +1 96626401000 protein targets using the chosen ligands. ext. 25123, Fax: +1 96626952521, e-mail: [email protected]; [email protected] and Dr. Mohammed H. AlQahtani, Cancer is a group of diseases caused by dysregulation in Director, Center of Excellence in Genomic Medicine Research, King molecular signaling pathways due to over- and underexpression Abdulaziz University, PO BOX 80216, Jeddah 21589, Kingdom of and loss/gain of function mutations of key proteins associated Saudi Arabia. Tel: +1 96626401000 ext. 25962, Fax: +1 96626952521, e-mail: [email protected] with altered cell growth and cell-cycle progression. It develops via a multi-step process of initiation, promotion, and progression Key Words: Kidney cancer, gene expression profiling, S100A8, (1, 2). Among all types of urological cancers, kidney cancer is docking, anticancer target, Saudi Arabia. the second leading cause of death in adults, mainly due to lack of 0250-7005/2014 $2.00+.40 1873 ANTICANCER RESEARCH 34: 1873-1884 (2014) promising biomarkers for effective target therapy. We conducted presence and concentration of free calcium molecules. S100A8 transcriptomic profiling and functional pathway analysis to study and S100A9 share strong sequence homology and can form the role of the S100A8 protein in tumor cells and in cancer heterodimers (without calcium) or heterotetramers (with development. Docking study revealed the potential of S100A8 calcium) (18). Three-dimensional crystallographic analysis as a target of therapeutic importance. reveals that calcium-bound C-terminal EF-hand loops are S100A8 is a low-molecular-weight proinflammatory protein necessary for tetramerization (33). Overall, this indicates that of 10 kDa, belonging to the S100 family of Ca2+-binding the S100A8, S100A9 or S100A8−S100A9 complex could be elongation factor (EF) hand-type proteins constitutively targeted to prevent the tumor cell migration and growth. expressed by myeloid cells, such as neutrophils and activated Molecular docking gives an optimized conformation and monocytes, under physiological conditions (3-6). However, relative orientation for both the protein and ligand molecule increased expression is seen in epithelial cells under pathological such that the free energy of the overall bound system is conditions, including inflammation and wound healing (7). minimal. Non-selective non-steroidal anti-inflammatory drugs S100A8 is an essential gene for life since S100A8 knock-out (NSAID) such as aspirin, diclofenac, indomethacin, ibuprofen mice die during embryonic development (8). Enhanced and naproxen inhibit both cyclooxygenase, COX-1 and COX2 expression of S100A8 is one of the hallmarks of chronic but can lead to drastic side-effects such as gastric ulceration. inflammation and epithelial cancer. Overexpression of S100A8 is However, selective NSAIDs such as celecoxib (Celebrex®) are found in various types of carcinomas, including breast (9-10), much safer and only inhibit COX2 found at sites of prostate (11-12), lung (13), gastric (14), hepatic (15), pancreatic inflammation, more than that which is normally found in the (16) and colorectal (17) cancer. Nevertheless, little research has stomach, blood platelets, and blood vessels (COX1). been carried out on its expression in different types of tumor Aspirin, a prototypical analgesic, is very commonly cells or its correlation with cancer development; the differential administered for the treatment of mild to moderate pain. It expression pattern or role of S100A8 in progression of kidney has anti-inflammatory and anti-pyretic properties and acts as cancer has not been reported as far as we are aware. an inhibitor of cyclooxygenase (both COX1 and COX2), Several lines of evidence point to vital functions of S100A8 which results in the inhibition of prostaglandin biosynthesis. during tumorigenesis and, although its exact role within the It also inhibits platelet aggregation and is used in the tumor environment is still not understood, different tumor- prevention of arterial and venous thrombosis. Daily aspirin promoting effects have been proposed. S100A8 preferentially intake has been shown to be beneficial in treatment of cancer forms heterodimeric complexes with S100A9 and lowering the risk of cancer development (34-37). The (S100A8−S100A9) (18), which undergoes conformational molecular mechanisms involved in anticancer action of changes upon Ca2+ binding and functions as a sensor of aspirin have not yet been elucidated. intracellular Ca2+ (19). Extracellularly, S100A8−S100A9 acts Dexamethasone, is a synthetic adrenocortical steroid (analog as ligand for different receptors, including the receptor for of glucocorticoids) primarily used for its anti-inflammatory advanced glycation end products (RAGE) (10, 20), toll like effects in disorders of many organ systems, and in receptor-4 (TLR4) (21), CD36 receptor (22) and NADPH immunomodulation, as it modifies the body’s immune responses oxidase (23). S100A8 exerts potent pro-inflammatory activity to diverse stimuli. It is an NSAID with anti-pyretic and analgesic (24-26), attracts neutrophils (27), influences myeloid cell actions used primarily in the treatment of chronic arthritic differentiation (28-29), affects transendothelial migration of conditions and certain soft tissue disorders associated with pain phagocytes (30) and induces expression of pro-inflammatory and inflammation. It acts by blocking the synthesis of mediators (31). Studies suggest S100A8 to be an important prostaglandins by inhibiting COX, which converts arachidonic driver of the inflammatory environment, ultimately promoting acid to cyclic endoperoxides, precursors of prostaglandins. cancer progression (10, 15). A recent study showed a role of Inhibition of prostaglandin synthesis accounts for its
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