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Eur Biophys J DOI 10.1007/s00249-013-0929-6 ORIGINAL PAPER Ribosylation of bovine serum albumin induces ROS accumulation and cell death in cancer line (MCF-7) Mohd Shahnawaz Khan • Sourabh Dwivedi • Medha Priyadarshini • Shams Tabrez • Maqsood Ahmed Siddiqui • Haseeb Jagirdar • Abdulrahman M. Al-Senaidy • Abdulaziz A. Al-Khedhairy • Javed Musarrat Received: 28 April 2013 / Revised: 30 July 2013 / Accepted: 10 September 2013 Ó European Biophysical Societies’ Association 2013 Abstract Formation of advanced glycation end products (AGE) is crucially involved in the several pathophysiologies associated with ageing and diabetes, for example arthritis, atherosclerosis, chronic renal insufficiency, Alzheimer’s disease, nephropathy, neuropathy, and cataracts. Because of devastating effects of AGE and the significance of bovine serum albumin (BSA) as a transport protein, this study was designed to investigate glycation-induced structural modifications in BSA and their functional consequences in breast cancer cell line (MCF-7). We incubated D-ribose with BSA and monitored formation of D-ribose-glycated BSA by observing changes in the intensity of fluorescence at 410 nm. NBT (nitro blue tetrazolium) assay was performed to confirm formation of keto-amine during glycation. Absorbance at 540 nm (fructosamine) increased markedly with time. Furthermore, intrinsic protein and 8-anilino-1-naphthalenesulfonate (ANS) fluorescence revealed marked conformational changes in BSA upon ribosylation. In addition, a fluorescence assay with thioflavin T (ThT) revealed a remarkable increase in fluorescence at 485 nm in the presence of glycated BSA. This suggests that glycation with Dribose induced aggregation of BSA into amyloid-like deposits. Circular dichroism (CD) study of native and ribosylated BSA revealed molten globule formation in the glycation pathway of BSA. Functional consequences of ribosylated BSA on cancer cell line, MCF-7 was studied by MTT assay and ROS estimation. The results revealed cytotoxicity of ribosylated BSA on MCF-7 cells. M. S. Khan (&) H. Jagirdar A. M. Al-Senaidy Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia e-mail: [email protected] Non-enzymatic glycation is a complex cascade of reactions initiated by condensation of reducing sugars with the free amino groups of proteins to form reversible Schiff’s bases which undergo rearrangement to form relatively stable Amadori products. Amadori products, over a period of time, undergo a series of reactions involving multiple dehydration, fragmentation, and oxidative modification via highly reactive dicarbonyl intermediates to form stable, heterogeneous adducts called advanced glycation end products (AGE) (Sing et al. 2001; Baynes et al. 1989; Monnier 1989). Although AGE formation occurs during the normal ageing process, it is accelerated under hyperglycemic conditions. Further, it has been shown that formation of AGE in vivo contributes to several pathophysiologies associated with ageing and diabetes mellitus, for example arthritis, atherosclerosis, chronic renal insufficiency, Alzheimer’s disease, nephropathy, neuropathy, and cataracts S. Dwivedi M. A. Siddiqui A. A. Al-Khedhairy DNA Research Chair, Department of Zoology, King Saud University, Riyadh, Kingdom of Saudi Arabia M. Priyadarshini Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA S. Tabrez King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia J. Musarrat Department of Agricultural Microbiology, Aligarh Muslim University, Aligarh, India Keywords Glycation Bovine serum albumin Cytotoxicity Fluorescence Circular dichroism Introduction 123 Eur Biophys J (Vlassara 1996; Lyons et al. 1991; Brownlee 1995; Shuvaev et al. 2001; Luthra and Balasubramanian 1993; Kumar et al. 2004). In addition, many cells have receptors for AGE (RAGE). Interaction of AGE with RAGE leads to activation of NF-kB, which stimulates generation of the pro-inflammatory and adhesion molecules that underlie the pathology of diabetic vascular complications (Mrudula et al. 2007; Bengmark 2007). Moreover, abnormal modification, including glycation, induces neuronal proteins to misfold and form amyloid fibrils in a stepwise process from prefibrils to fibrils (Necula and Kuret 2004). Glycation alters the biological activity of proteins and degradation mechanisms. Protein cross-linking by glycation results in the formation of detergent-insoluble and protease-resistant aggregates. Therefore, the study of AGEs has become an important area of biomedical research. Although much work has been conducted on glycation of proteins with glucose, few research groups have attempted to study glycation by ribose and resulting effects on cell structure and function (Chanshuai et al. 2011). In recent years, ribosylation has attracted more attention because of its involvement in protein glycation and its subsequent effects, for example protein aggregation and production of reactive oxygen species (ROS) (Zhang et al. 2006; Li et al. 2007; Tan et al. 2007; Yan et al. 2012; Chen et al. 2009). D-Ribose is present in living cells and is important in life processes. It is the structural backbone of purines and pyrimidines, critical cellular compounds which are components of genetic material, and is a constituent of numerous cofactors, some vitamins, and adenosine triphosphate (ATP) the ‘‘energy currency’’ of the cell. Importantly, every cell needs D-ribose for essential activity. Levels of D-ribose in the blood and cerebrospinal fluid are 0.01–0.1 mM in healthy individuals (Seuffer 1977; Cai et al. 2005). Also, endogenous D-ribose can be produced from glucose via the hexose monophosphate shunt and is released from nucleotides during metabolic turnover. Although high levels of ribose have not been found in common diseases, according to van der Knaap et al. (1999) and Huck et al. (2004) a rare disease called ribose-5phosphate isomerase deficiency results in an increase in the polyols arabitol, ribitol, and erithrol, with white matter disorder. Furthermore, it has been reported that poly(ADPribosyl)ation of nuclear protein increases in Alzheimer’s disease (Love et al. 1999). Serum albumin comprises approximately 60 % of human plasma protein and its concentration is the major contributor to the oncotic pressure of blood. It is particularly sensitive to glycation. Marked structural and functional changes occur in BSA upon glycation. In vivo, the proportion of glycated albumin in healthy persons is in the range between 1 and 10 % (Shaklai et al. 1984; Peters 123 1996). However, among individuals with hyperglycemia it can increase two to threefold (Woodside et al. 1998; Bourdon et al. 1999). For this reason serum albumin has been adopted as a model in many in-vitro studies on glycation (Syrovy 1994; Culbertson et al. 2003). Here we investigate ribosylation induced structural modifications in BSA and its resultant effects on MCF-7 cells. Materials and methods The reducing monosaccharide ribose was purchased from Amresco (USA). BSA, thioflavin T, and MTT dye were from Sigma (USA) and Aldrich (USA). Other chemicals were of analytical grade. Glycation of bovine serum albumin (BSA) BSA was dissolved in phosphate-buffered-saline (pH 7.4) to yield 100 mg/ml stock solution. This solution was then mixed with ribose prepared in PBS (pH 7.4) to a final concentration of 50 mg/ml BSA and 1 M ribose. BSA alone and in the presence of ribose was used as control. Reaction mixtures were incubated at 37 °C for 0–21 days. All solutions were filtered through 0.22 lm membranes (Millipore, USA). Characterization of ribosylated BSA 1. 2. 3. SDS-PAGE analysis of native and glycated BSA: Aliquots of native and glycated BSA incubated for different times were subjected to 12 % SDS-PAGE. After electrophoresis, the gel was stained with Coomassie brilliant blue (CBB). Protein molecular weight markers were run to compare differences in molecular weights of native and glycated BSA. Fluorescence measurements: Fluorescence of the advanced glycated end-products was monitored by use of an F-4500 fluorophotometer (Hitachi, Japan). The excitation wavelength, kex, was 320 nm and emission was recorded in the range 335–500 nm (Coussons et al. 1997). The desired final protein concentration was 2 lM. Both excitation and emission slit widths were 5 nm. Nitroblue tetrazolium (NBT) assay: The extent of glycation of BSA incubated with ribose was assessed by NBT assay (Mendez et al. 2005). 200 ll 0.75 mM NBT was added to a 96-well microplate with 10 ll sample or standard. The kinetics of NBT reduction by fructosamine was studied by absorbance changes at 540 nm, after incubation for 30 min at 37 °C, by use of an MK3 microplate reader (Thermo, USA). Standard curves were generated by addition of Eur Biophys J 10 ml 1-deoxy-1-morpholino-D-fructose Sigma–Aldrich, USA). (1-DMF; Glycation-induced tertiary structure change in BSA 1. 2. Intrinsic fluorescence analysis: Intrinsic fluorescence of native and glycated BSA (2 lM) was monitored by use of an F-4500 fluorescence spectrophotometer (Hitachi, Japan). The emission spectrum from 300 to 400 nm was recorded after excitation at 280 and 295 nm at 25 °C. Extrinsic (ANS) fluorescence measurement: A stock solution of 1 mM ANS (Sigma, USA) was prepared in 20 mM Tris–HCl (pH 7.4). BSA (2 lM) and ANS (100 lM, Sigma–Aldrich) were mixed at room temperature for 1 h, and the fluorescence was subsequently measured by recording the emission spectrum from 400 to 600 nm (kex = 350 nm). Glycation-induced secondary structure change in BSA Circular dichroism measurement: Far-UV CD measurements were performed by use of a circular dichroism chiroptical spectrometer (Applied Photophysics, Chirascan-Plus, UK). Samples in a 1 mm quartz cuvette were maintained at 25 °C with a circulating water bath. Spectra of ribosylated BSA (0.2 mg/ml) at different times were measured in the range 190–250 nm with a step size of 1.0 nm. Each measurement was repeated thrice and averaged. Ribosylation-induced amyloid structure in BSA either exposed or not exposed to the glycated protein (0–40 lM) for 24 h. The culture medium was then changed to DMEM containing 10 % fetal bovine serum. MTT (final concentration 0.5 mg/ml; 50 ll) was added after adding the glycated protein. Plates were incubated at 37 °C for 4 h, then the assay was stopped by replacement of the MTT-containing medium with 150 ll dimethyl sulfoxide (DMSO) and absorbance at 540 nm was recorded by use of a Multiscan MK3 (Thermo Electron Corporation, USA). Reactive oxygen species (ROS) measurement: The level of cytosolic ROS was measured by use of DCFH-DA (Beyotime, China) as described by Smith et al. (2005). Briefly, MCF-7 cells were grown in a 24-well plate and incubated with ribose, BSA, and ribose-glycated BSA for 24 h. Normal cells were used as controls. Cells were washed with PBS and incubated with DCFH-DA for 30 min. DCFH-DA was initially nonfluorescent and was converted by oxidation to the fluorescent molecule DCFH (kex 485 nm/kem 538 nm). DCFH was then quantified by use of a CytoFluor multi-well plate reader (Fluoroskan Ascent, Thermo Lab Systems, USA). Results and discussion Glycation of serum albumin has been widely studied in recent years (Day et al. 1979; Luciano Viviani et al. 2008) and bovine serum albumin (BSA) is commonly used as molecular model. Epidemiological studies have established that reduced levels of serum albumin are associated with an increased mortality risk. Moreover, in the diseased population and in the general population, it has been estimated that the odds of death increase by approximately 50 % for Thioflavin T binding assay: Free ThT has excitation and emission maxima at 350 and 450 nm, respectively. However, upon binding to fibrils the excitation and emission maxima change to 450 and 485 nm, respectively (Naiki et al. 1989). Native and glycated BSA samples (5 ll) were added to solution containing 20 lM ThT in 20 mM TrisHCl buffer, pH 7.4, and shaken a few times before measurement of fluorescence at room temperature. A background fluorescence spectrum obtained by running blank buffer was subtracted from each sample fluorescence spectrum. The excitation wavelength was 444 nm, and emission was recorded at 482 nm. Fluorescence intensity at 482 nm was plotted against time. Cytotoxicity of ribosylated BSA to breast cancer cell line MCF-7 Cell viability (MTT) assay: MCF-7 cells were seeded on a 96-well plate at a concentration of 105 cells per well and Fig. 1 Changes in fluorescence during protein riboslyation. BSA (0.75 mM) was incubated with 1 M D-ribose at 37 °C and aliquots were taken at different times. Glycophore fluorescence was measured at kex 320 and spectra were recorded between 320 and 500 nm. The protein concentration used was 2 lM 123 Eur Biophys J each 2.5 % g/l decrement in the initial albumin level. Importantly, human serum albumin have extensive structural similarity (Brown 1976), so BSA instead of HSA was used in this study because of its low cost and ready availability. According to Liu and Metzger (2007), glycation of a protein produces a new fluorescence derivative (kex 320 nm, kem 410 nm), and thus fluorescence is commonly used to monitor the formation of AGEs. As shown in Fig. 1, fluorescence of ribose-glycated BSA increased markedly with time. BSA alone, used as a negative control, did not fluoresce at 410 nm. The increase (%) in the relative intensity of the fluorescence for ribose-glycated BSA was rapid, with an increase of 16 %/day during the incubation period. Interestingly, ribosylation of BSA starts very early from the first day of incubation and maximum fluorescence is reached after 14 days. However, fluorescence intensity decreases from days 21 to 30; this might be because of protein precipitation and aggregation with more days of incubation and/or reaction. Our results clearly demonstrate ribosylation is rapid, owing to the non-planar nature of ribose which provides more flexibility to react with proteins and other biomolecules, including DNA. Fructosamine is a common product of glycation, and the fructosamine content of a given protein reflects its degree of glycation (Mosca et al. 1987; Baker et al. 1985). Assay of fructosamine with nitroblue tetrazolium (NBT) is based on a color change correlated with Fig. 2 Detection of AGE by NBT assay The conditions for glycation of BSA were the same as for Fig. 1. Fructosamine was assayed with nitroblue tetrazolium. The kinetics of reduction of NBT by the fructosamine group (0.1 M carbonate buffer, pH 10.35) were measured at 540 nm after incubation for 30 min at 37 °C. Standard curves were generated by addition of 10 ml 1-deoxy-1-morpholino-Dfructose Fig. 3 SDS-PAGE analysis of native and glycated BSA. 12 % SDSPAGE was run for native and ribosylated BSA. Aliquots of ribosylated BSA incubated for different times were taken and 20 lg of protein was loaded into each lane. The first lane contains protein molecular weight marker. The next lane contains native BSA alone, used as control. The other lanes contain ribosylated BSA after incubation for 1, 2, 3, 7, 14 and 21 days 123 Fig. 4 Conformational changes in glycated BSA observed by measurement of intrinsic fluorescence. Experimental conditions were the same as those used for Fig. 1. Fluorescence spectra of BSA glycated with D-ribose after different reaction times: a excitation wavelength 280 nm; b excitation wavelength 295 nm. The protein concentration used was 2 lM and excitation and emission slits were set at 5 nm Eur Biophys J reduction of NBT to monoformazan by Amadori rearrangement products in alkaline buffer. Here, we used NBT to monitor the time course of formation of fructosamine during glycation. As shown in Fig. 2, absorbance at 540 nm increased markedly with time. Absorbance increased rapidly on day 1 and then gradually reached a plateau. The increase in absorbance demonstrates formation of advanced glycation end products after reaction of ribose with BSA. SDS-PAGE analysis of native and glycated BSA at different times (Fig. 3) revealed structural change in BSA and changes of apparent molecular weight after ribosylation. Retardation of protein bands was observed during Fig. 5 a Changes in ANS fluorescence of BSA during glycation. Experimental conditions were the same as those used for Fig. 1. ANS (100 lM) was added to samples of ribosylated BSA for different times. Fluorescence spectra of ANS were recorded at kex 350 nm. The concentration of BSA used was 2 lM. b Changes in the fluorescence of thioflavin T in the presence of ribosylated BSA after different times. ThT (20 lM) was added to samples of BSA in different concentrations of D-ribose for different times. The intensity of ThT fluorescence was recorded (kex 444 nm; kem 482 nm). The concentration of BSA used was 2 lM glycation of BSA in the presence of ribose. The increasing molecular weight of BSA probably resulted from bound ribose. Furthermore, protein degradation could also be seen from 14th and 21st day of incubation. To investigate whether ribosylation induced a change in the tertiary structure of BSA, we took aliquots after different incubation times and measured the intrinsic fluorescence of the protein (total protein fluorescence at kex 280 nm, kem 300–400 nm, and tryptophan fluorescence at kex 295 nm). As depicted in Fig. 4a, the intensity of intrinsic fluorescence decreased when BSA was incubated with D-ribose for different times. Also, the environment of tryptophan residues was perturbed in the presence of ribose. The decrease in fluorescence intensity (Fig. 4b) reaffirms the change in the environment of aromatic residues as a result of ribosylation. It is also indicative of the increase in polarity caused by ribose binding. The fluorescent molecule 8-anilino-1-naphthalenesulfonate (ANS), which is frequently used to demonstrate the presence of partially folded conformations of globular proteins (Matulis and Lovrien 1998), was used to clarify whether any hydrophobic patches become exposed at the exterior of the BSA. Figure 5a shows that ribosylation increased the ANS fluorescence intensity just after (i.e. on the first day) incubation with ribose. Thereafter, the ANS fluorescence intensity decreased with incubation time. These results are indicative of biphasic change in the conformation of BSA after ribosylation. Also, hydrophobic patches are more exposed at the surface which further leads to protein aggregation. For investigation of ribosylationinduced protein aggregation and amyloid formation, we used the thioflavin T binding assay. Our results demonstrate that D-ribose reacted quickly with BSA to promote Fig. 6 Far-UV circular dichroism analysis of ribosylated BSA was performed on a Chirascan-Plus (Applied Photophysics, UK) circular dichroism spectrometer. Samples in a 1 mm quartz cuvette were maintained at 25 °C. Spectra (190–250 nm; step size 1.0 nm) of native and ribosylated BSA (0.2 mg/ml) were measured at different times. Each measurement was repeated three times and averaged 123 Eur Biophys J aggregation of glycated products into ThT-positive aggregates (Fig. 5b). Far UV-CD was used to determine the secondary structure content of proteins. On the basis of secondary structure, several classes of proteins were used in this study including a-class, b-class, a ? b class, and proteins with pronounced random coil conformation. a-class and a ? b class proteins furnish two negative peaks, one at 208 nm and other at 222 nm, whereas b-class proteins furnish a single negative peak between 215 and 222 nm. Random Fig. 7 Effect of ribosylated BSA on the viability of breast cancer cell line MCF-7. Cell viability of MCF-7 cells was measured after adding 0.5–40 lM ribosylated BSA. a Morphological change in MCF-7 after seeding with glycated-BSA. b Cell viability of MCF-7 in the presence of gly-BSA 123 coil proteins give a single negative peak at approximately 200 nm. The far UV-CD result (Fig. 6) reveals a pronounced conformational change (increase in alpha helicity) of BSA after incubation with ribose for 7 days. A second transition is observed after ribosylation for 14–30 days. The effect of ribosylated BSA on the viability of MCF-7 cells was examined by use of the MTT assay. Reduction in cell viability was measured in the presence of ribosylated BSA after glycation for 1–21 days (Fig. 7). The number of viable cells decreased significantly when the cells were Eur Biophys J Fig. 8 Measurement of reactive oxygen species in MCF-7 cells treated with glycated BSA. a Morphological change in MCF-7 in the absence and presence of Gly-BSA: a, BSA alone; b, Gly-BSA after 7 days; c, Gly-BSA after 14 days; d, Gly-BSA after 21 days. b Fluorescence measurement of DCF in MCF-7 cell lines. S1, GlyBSA after 7 days; S2, Gly-BSA after 14 days; S3, Gly-BSA after 21 days incubated with ribosylated BSA, whereas cell viability did not significantly change in the presence of native BSA or Dribose (Fig. 7a, b). The reduction in cell viability induced by ribosylated BSA was concentration-dependent. To identify the cause of cytotoxicity, we measured ROS content; the results were indicative of an increase in fluorescence of DCF (Fig. 8b) after incubation of cells with ribosylated BSA. The increase in ROS is clearly apparent from the morphology of MCF-7 cells, and the extent of the change increases with incubation time with glycated-BSA (Fig. 8a). The increase in ROS is maximum with glycatedBSA formed after 21 days. Many studies have shown that glycation leads to the production of ROS, which are harmful to cellular metabolism and cause cell damage (Sakurai and Tsuchiya 1988; Yan et al. 1994; Heath et al. 1996). Much attention has been devoted to study of the production of hydroxyl radicals via glycation, and inhibition of subsequent damage caused by them (Kikuchi et al. 2003; Chetyrkin et al. 2008). Some diseases, for example Alzheimer’s disease, transmissible spongiform encephalopathies, pancreatic islet amyloidosis, and familial amyloidosis are caused primarily by aggregation of amyloid-like fibrils in organs and in the circulation (Jackson and Clarke 2000). Recently, it has been documented that amyloid-like fibrils are cytotoxic to neuronal cells, BHK-21 cells, SKOV-3, and cancer cells (Gharibyan et al. 2007; Zamotin et al. 2006). Whether fibrillar proteins can be used as anti-cancer drugs in cancer therapy is unclear. This work reaffirms the previously stated hypothesis of amyloid like aggregation in proteins upon glycation and hints at the development of prospective anti breast cancer drugs. Acknowledgment The authors extend their appreciation to the Deanship of Scientific Research at KSU for funding this work through research group project number RGP-VPP-215. 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