Browsing by Author "Cetin Atalay, R."
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Item Open Access Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism?(American Association for Cancer Research, 2003) Irmak, M. B.; Ince, G.; Ozturk, M.; Cetin Atalay, R.Selenium is essential to human health, and its deficiency is associated with different diseases including liver necrosis. Selenium is protective against viral hepatitis and hepatocellular carcinoma (HCC). The underlying molecular mechanisms of selenium effects are not well known. In this study, in vitro response of HCC-derived cell lines to selenium deficiency is examined alone or in conjunction with Vitamin E and copper/zinc. Here, we show that itt vitro selenium deficiency in a subset of HCC-derived cell lines causes oxidative stress and cytochrome c release with subsequent cell death by apoptosis. The oxidative stress and consequent cell death induced by selenium deficiency on these cells are reverted by the antioxidant effect of Vitamin E. However, most HCC cell lines (10 of 13) tolerate selenium deficiency. Consequently, they escape apoptosis. Moreover, nine of these tolerant cell lines have integrated hepatitis B Virus (HBV) DNA in their genomes, and some display p53-249 mutation, indicating past exposure to HBV or aflatoxins, established factors for oxidative stress and cancer risk in liver. An HBV-transfected clone (2.2.15) of the sensitive HepG2 cell line has gained tolerance to selenium deficiency. Our findings indicate that selenium deficiency induces apoptosis in some "hepatocyte-like" cells. However, most HCC cells, particularly HBV-related ones, tolerate selenium deficiency and escape its deadly consequences. Thus, as demonstrated by the gain of survival capacity of apoptosis-sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative-stress conditions.Item Open Access Cytotoxic activities of some novel benzhydrylpiperazine derivatives(Georg Thieme Verlag, 2013) Gurdal, E. E.; Yarim, M.; Durmaz, I.; Cetin Atalay, R.This study presents the synthesis of nineteen 1-(substitutedbenzoyl)-4- benzhydrylpiperazine and 1-[(substitutedphenyl)sulfonyl]-4-benzhydrylpiperazine derivatives. In vitro cytotoxic activities of the compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Among the test compounds, benzamide derivatives had high cytotoxic activity whereas sulfonamide derivatives showed variable 50% growth inhibition (GI50). © Georg Thieme Verlag KG Stuttgart · New York.Item Open Access Data sources and computational approaches for generating models of gene regulatory networks(2005) Aguda, B. D.; Craciun, G.; Cetin Atalay, R.; Lipkowitz K.B.Larter R.Cundari T.R.[No abstract available]Item Open Access The design and cytotoxic evaluation of some 1-aryl-3-isopropylamino-1-propanone hydrochlorides towards human Huh-7 hepatoma cells(Wiley, 2011) Mete, E.; Gul, H. I.; Cetin Atalay, R.; Das, U.; Sahin, E.; Gul, M.; Kazaz, C.; Dimmock, J. R.A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated. A number of Mannich bases displayed greater potency than the reference drug 5-fluorouracil against human Huh-7 hepatoma cells. In particular, 1i emerged as a lead compound possessing 2.8 fold higher activity than that of the reference drug. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Item Open Access Dual functionality of conjugated polymer nanoparticles as an anticancer drug carrier and a fluorescent probe for cell imaging(Royal Society of Chemistry, 2014) Gezici, Ö.; Durmaz, I.; Güven, E. B.; Ünal, Ö.; Özgün, A.; Cetin Atalay, R.; Tuncel, D.Multifunctional nanoparticles based on a green emitting, hydrophobic conjugated polymer, poly[(9,9-bis{propeny}fluorenyl-2,7-diyl)-co-(1,4-benzo-{2,1,3}-thiodiazole)] (PPFBT), that acts both as a fluorescent reporter and a matrix to accommodate an anti-cancer compound, camptothecin (CPT), were prepared, characterized and their potential as a fluorescent probe for cell imaging and as a drug delivery vehicle were evaluated via in vitro cell assays. The cell viability of human hepatocellular carcinoma cell line (Huh7) was investigated in the absence and presence of CPT with sulforhodamine B (SRB) and real-time cell electronic sensing (RT-CES) cytotoxicity assays.Item Open Access Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis(PLOS ONE, 2013) Yildiz, G.; Arslan Ergul, A.; Bagislar, S.; Konu, O.; Yuzugullu, H.; Gursoy Yuzugullu, O.; Ozturk, N.; Ozen, C.; Ozdag, H.; Erdal, E.; Karademir, S.; Sagol, O.; Mizrak, D.; Bozkaya, H.; Ilk, H. G.; Ilk, O.; Bilen, B.; Cetin Atalay, R.; Akar, N.; Ozturk, M.Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.Item Open Access Identification of Novel Reference Genes Based on MeSH Categories(PLoS ONE, 2014) Ersahin, T.; Carkacioglu, L.; Can, T.; Konu, O.; Atalay, V.; Cetin Atalay, R.Transcriptome experiments are performed to assess protein abundance through mRNA expression analysis. Expression levels of genes vary depending on the experimental conditions and the cell response. Transcriptome data must be diverse and yet comparable in reference to stably expressed genes, even if they are generated from different experiments on the same biological context from various laboratories. In this study, expression patterns of 9090 microarray samples grouped into 381 NCBI-GEO datasets were investigated to identify novel candidate reference genes using randomizations and Receiver Operating Characteristic (ROC) curves. The analysis demonstrated that cell type specific reference gene sets display less variability than a united set for all tissues. Therefore, constitutively and stably expressed, origin specific novel reference gene sets were identified based on their coefficient of variation and percentage of occurrence in all GEO datasets, which were classified using Medical Subject Headings (MeSH). A large number of MeSH grouped reference gene lists are presented as novel tissue specific reference gene lists. The most commonly observed 17 genes in these sets were compared for their expression in 8 hepatocellular, 5 breast and 3 colon carcinoma cells by RT-qPCR to verify tissue specificity. Indeed, commonly used housekeeping genes GAPDH, Actin and EEF2 had tissue specific variations, whereas several ribosomal genes were among the most stably expressed genes in vitro. Our results confirm that two or more reference genes should be used in combination for differential expression analysis of large-scale data obtained from microarray or next generation sequencing studies. Therefore context dependent reference gene sets, as presented in this study, are required for normalization of expression data from diverse technological backgrounds. © 2014 Ersahin et al.Item Open Access Image classification of human carcinoma cells using complex wavelet-based covariance descriptors(Public Library of Science, 2013-01-16) Keskin, F.; Suhre, A.; Kose, K.; Ersahin, T.; Çetin, A. Enis; Cetin Atalay, R.Cancer cell lines are widely used for research purposes in laboratories all over the world. Computer-assisted classification of cancer cells can alleviate the burden of manual labeling and help cancer research. In this paper, we present a novel computerized method for cancer cell line image classification. The aim is to automatically classify 14 different classes of cell lines including 7 classes of breast and 7 classes of liver cancer cells. Microscopic images containing irregular carcinoma cell patterns are represented by subwindows which correspond to foreground pixels. For each subwindow, a covariance descriptor utilizing the dual-tree complex wavelet transform (DT-CWT) coefficients and several morphological attributes are computed. Directionally selective DT-CWT feature parameters are preferred primarily because of their ability to characterize edges at multiple orientations which is the characteristic feature of carcinoma cell line images. A Support Vector Machine (SVM) classifier with radial basis function (RBF) kernel is employed for final classification. Over a dataset of 840 images, we achieve an accuracy above 98%, which outperforms the classical covariance-based methods. The proposed system can be used as a reliable decision maker for laboratory studies. Our tool provides an automated, time-and cost-efficient analysis of cancer cell morphology to classify different cancer cell lines using image-processing techniques, which can be used as an alternative to the costly short tandem repeat (STR) analysis. The data set used in this manuscript is available as supplementary material through http://signal.ee.bilkent.edu.tr/cancerCellLineClassificationSampleImages.html.Item Open Access Implicit motif distribution based hybrid computational kernel for sequence classification(Oxford University Press, 2005) Atalay, V.; Cetin Atalay, R.Motivation: We designed a general computational kernel for classification problems that require specific motif extraction and search from sequences. Instead of searching for explicit motifs, our approach finds the distribution of implicit motifs and uses as a feature for classification. Implicit motif distribution approach may be used as modus operandi for bioinformatics problems that require specific motif extraction and search, which is otherwise computationally prohibitive. Results: A system named P2SL that infer protein subcellular targeting was developed through this computational kernel. Targeting-signal was modeled by the distribution of subsequence occurrences (implicit motifs) using self-organizing maps. The boundaries among the classes were then determined with a set of support vector machines. P2SL hybrid computational system achieved ∼81% of prediction accuracy rate over ER targeted, cytosolic, mitochondrial and nuclear protein localization classes. P2SL additionally offers the distribution potential of proteins among localization classes, which is particularly important for proteins, shuttle between nucleus and cytosol. © The Author 2004. Published by Oxford University Press. All rights reserved.Item Open Access Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status(Springer, 2011) Buontempo, F.; Ersahin, T.; Missiroli, S.; Senturk, S.; Etro, D.; Ozturk, M.; Capitani, S.; Cetin Atalay, R.; Neri, M. L.The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is involved in cell survival and anti-apoptotic signaling. Akt has been shown to be constitutively expressed in a variety of human tumors including hepatocellular carcinoma (HCC). In this report we analyzed the status of Akt pathway in three HCC cell lines, and tested cytotoxic effects of Akt pathway inhibitors LY294002, Wortmannin and Inhibitor VIII. In Mahlavu human hepatoma cells Akt was constitutively activated, as demonstrated by its Ser473 phosphorylation, downstream hyperphosphorylation of BAD on Ser136, and by a specific cell-free kinase assay. In contrast, Huh7 and HepG2 did not show hyperactivation when tested by the same criteria. Akt enzyme hyperactivation in Mahlavu was associated with a loss of PTEN protein expression. Akt signaling was inhibited by the upstream kinase inhibitors, LY294002, Wortmannin, as well as by the specific Akt Inhibitor VIII in all three hepatoma cell lines. Cytotoxicity assays with Akt inhibitors in the same cell lines indicated that they were all sensitive, but with different IC50 values as assayed by RT-CES. We also demonstrated that the cytotoxic effect was through apoptotic cell death. Our findings provide evidence for its constitutive activation in one HCC cell line, and that HCC cell lines, independent of their Akt activation status respond to Akt inhibitors by apoptotic cell death. Thus, Akt inhibition may be considered as an attractive therapeutic intervention in liver cancer. © Springer Science+Business Media, LLC 2010.Item Open Access Iterative H-minima-based marker-controlled watershed for cell nucleus segmentation(John Wiley & Sons, Inc., 2016) Koyuncu, Can Fahrettin; Akhan, Ece; Ersahin, T.; Cetin Atalay, R.; Gunduz Demir, ÇiğdemAutomated microscopy imaging systems facilitate high-throughput screening in molecular cellular biology research. The first step of these systems is cell nucleus segmentation, which has a great impact on the success of the overall system. The marker-controlled watershed is a technique commonly used by the previous studies for nucleus segmentation. These studies define their markers finding regional minima on the intensity/gradient and/or distance transform maps. They typically use the h-minima transform beforehand to suppress noise on these maps. The selection of the h value is critical; unnecessarily small values do not sufficiently suppress the noise, resulting in false and oversegmented markers, and unnecessarily large ones suppress too many pixels, causing missing and undersegmented markers. Because cell nuclei show different characteristics within an image, the same h value may not work to define correct markers for all the nuclei. To address this issue, in this work, we propose a new watershed algorithm that iteratively identifies its markers, considering a set of different h values. In each iteration, the proposed algorithm defines a set of candidates using a particular h value and selects the markers from those candidates provided that they fulfill the size requirement. Working with widefield fluorescence microscopy images, our experiments reveal that the use of multiple h values in our iterative algorithm leads to better segmentation results, compared to its counterparts.Item Open Access Liver cancer cells are sensitive to Lanatoside C induced cell death independent of their PTEN status(Elsevier, 2016) Durmaz, I.; Guven, E. B.; Ersahin, T.; Ozturk, M.; Calis, I.; Cetin Atalay, R.Background Hepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. Hypothesis It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Methods Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. Results In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. Conclusion The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. © 2015 Elsevier GmbH. © 2016 Elsevier GmbH. All rights reserved.Item Open Access Molecular characterization of a full genome Turkish hepatitis C virus 1b isolate (HCV-TR1): A predominant viral form in Turkey(Kluwer Academic Publishers, 2002) Yıldız, E.; Oztan, A.; Sar, F.; Pınarbası, E.; Cetin Atalay, R.; Akkız, H.; Ozturk, M.Based on direct sequencing information from 5′UTR and NS5B regions, we identified subtype 1b as a predominant hepatitis C virus genome in Turkey, which affected more than 91% of 79 patients studied. Next, the full genome sequence of a Turkish 1b isolate was obtained by the cloning of polypeptide-encoding region into 7 overlapping fragments. Turkish 1b isolate, which was named HCV-TR1, comprises 9361 nucleotides, including 306 nucleotides of 5′UTR, a single long open reading frame of 9033 nucleotides, and 22 nucleotides of 3′UTR. When compared to HCV 1b polypeptide sequences available at GenBank, the predicted polypeptide displayed a total of 36 amino acid substitutions, of which 16 was specific for HCV-TR1 isolate. Despite these changes, major structural and functional motifs of HCV proteins were maintained in HCV-TR1. In contrast, HCV-TR1 displayed amino acid substitutions in 6 out of 9 major cytotoxic T-cell epitopes. These data suggest that HCV-TR1 encodes functionally intact viral proteins, but it also encodes altered viral epitopes, which may affect host immune-response.Item Open Access A monoclonal antibody against DNA binding helix of p53 protein(Nature Publishing Group, 2001) Yolcu, E.; Sayan, B. S.; Yağci, T.; Cetin Atalay, R.; Soussi, T.; Yurdusev, N.; Ozturk, M.Three monoclonal antibodies (Mabs) were generated against p53 DNA-binding core domain. When tested by immunoprecipitation, Western blot and immunofluorescence techniques, Mab 9E4, as well as 7D3 and 6B10 reacted with both wild-type and various mutant p53 proteins. The epitopes recognized by Mabs 7D3, 9E4 and 6B10 were located respectively within the amino acid residues 211-220, 281-290 and 291-300 of human p53 protein. The epitope recognized by 9E4 Mab coincides with helix 2, also called p53 DNA binding helix, which allows the direct contact of the protein with its target DNA sequences. This antibody may be useful to study transcription-dependent and transcription-independent activities of wild-type and mutant p53 proteins.Item Open Access Near-IR absorbing BODIPY derivatives as glutathione-activated photosensitizers for selective photodynamic action(Wiley-VCH Verlag, 2014) Turan, I. S.; Cakmak, F. P.; Yildirim, D. C.; Cetin Atalay, R.; Akkaya, E. U.Enhanced spatiotemporal selectivity in photonic sensitization of dissolved molecular oxygen is an important target for improving the potential and the practical applications of photodynamic therapy. Considering the high intracellular glutathione concentrations within cancer cells, a series of BODIPY-based sensitizers that can generate cytotoxic singlet oxygen only after glutathione-mediated cleavage of the electron-sink module were designed and synthesized. Cell culture studies not only validate our design, but also suggest an additional role for the relatively hydrophobic quencher module in the internalization of the photosensitizer.Item Open Access A novel thiazolidine compound induces caspase-9 dependent apoptosis in cancer cells(Elsevier, 2012) Onen-Bayram, F. E.; Durmaz, I.; Scherman, D.; Herscovici, J.; Cetin Atalay, R.The forward chemogenomics strategy allowed us to identify a potent cytotoxic thiazolidine compound as an apoptosis-inducing agent. Chemical structures were designed around a thiazolidine ring, a structure already noted for its anticancer properties. Initially, we evaluated these novel compounds on liver, breast, colon and endometrial cancer cell lines. The compound 3 (ALC67) showed the strongest cytotoxic activity (IC50 ∼5 μM). Cell cycle analysis with ALC67 on liver cells revealed SubG1/G1 arrest bearing apoptosis. Furthermore we demonstrated that cytotoxicity of this compound was due to the activation of caspase-9 involved apoptotic pathway, which is death receptor independent. © 2012 Elsevier Ltd. All rights reserved.Item Open Access Nuclear exclusion of p33ING1b tumor suppressor protein: explored in HCC cells using a new highly specific antibody(Mary Ann Liebert, Inc, 2009) Sayan, B.; Emre, N. C. T.; Irmak, M. B.; Ozturk, M.; Cetin Atalay, R.Mouse monoclonal antibodies (MAb) were generated against p33ING1b tumor suppressor protein. 15B9 MAb was highly specific in recognizing a single protein band of ∼33 kDa endogenous p33ING1b protein from HCC cell lines and normal liver tissue by Western blot analysis and by immunoprecipitation. Although p33ING1b mutations are rarely observed in cancer, differential subcellular distribution and nuclear exclusion of p33ING1b were reported in different cancer types. Therefore we analyzed the expression and subcellular localization of p33ING1b in HCC cell lines using 15B9 MAb. So far, p33ING1b mutations or differential subcellular localization are not reported in HCC. In this study, by indirect immunofluorescence using MAb 15B9, we demonstrate that nuclear localization of p33ING1b was highly correlated with well-differentiated HCC cell lines whereas poorly differentiated HCC cells have nuclear exclusion of the protein. Moreover no association was observed between differential subcellular localization of p33ING1b and p53 mutation status of HCC cell lines. Hence our newly produced MAb 15B9 can be used for studying cellular activities of p33ING1b under normal and cancerous conditions. © Copyright 2009, Mary Ann Liebert, Inc.Item Open Access Object-oriented segmentation of cell nuclei in fluorescence microscopy images(Wiley-Liss, 2018) Koyuncu, Can Fahrettin; Cetin Atalay, R.; Gunduz Demir, CigdemCell nucleus segmentation remains an open and challenging problem especially to segment nuclei in cell clumps. Splitting a cell clump would be straightforward if the gradients of boundary pixels in-between the nuclei were always higher than the others. However, imperfections may exist: inhomogeneities of pixel intensities in a nucleus may cause to define spurious boundaries whereas insufficient pixel intensity differences at the border of overlapping nuclei may cause to miss some true boundary pixels. In contrast, these imperfections are typically observed at the pixel-level, causing local changes in pixel values without changing the semantics on a large scale. In response to these issues, this article introduces a new nucleus segmentation method that relies on using gradient information not at the pixel level but at the object level. To this end, it proposes to decompose an image into smaller homogeneous subregions, define edge-objects at four different orientations to encode the gradient information at the object level, and devise a merging algorithm, in which the edge-objects vote for subregion pairs along their orientations and the pairs are iteratively merged if they get sufficient votes from multiple orientations. Our experiments on fluorescence microscopy images reveal that this high-level representation and the design of a merging algorithm using edge-objects (gradients at the object level) improve the segmentation results.Item Open Access pH-responsive near-infrared emitting conjugated polymer nanoparticles for cellular imaging and controlled-drug delivery(John Wiley and Sons Inc., 2014) Pennakalathil, J.; Özgün, A.; Durmaz, I.; Cetin Atalay, R.; Tuncel, D.In this article, pH-responsive near-infrared emitting conjugated polymer nanoparticles (CPNs) are prepared, characterized, and their stabilities are investigated under various conditions. These nanoparticles have capacity to be loaded with water insoluble, anticancer drug, camptothecin (CPT), with around 10% drug loading efficiency. The in vitro release studies demonstrate that the release of CPTs from CPNs is pHdependent such that significantly faster drug release at mildly acidic pH of 5.0 compared with physiological pH 7.4 is observed. Time and dose-dependent in vitro cytotoxicity tests of blank and CPT-loaded nanoparticles are performed by realtime cell electronic sensing (RT-CES) assay with hepatocellular carcinoma cells (Huh7). The results indicate that CPNs can be effectively utilized as vehicles for pH-triggered release of anticancer drugs.Item Open Access Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells(National Academy of Sciences, 2006) Ozturk, N.; Erdal, E.; Mumcuoglu, M.; Akcali, K. C.; Yalcin, O.; Senturk, S.; Arslan-Ergul, A.; Gur, B.; Yulug, I.; Cetin Atalay, R.; Yakicier, C.; Yagci, T.; Tez, M.; Ozturk, M.Tumor cells have the capacity to proliferate indefinitely that is qualified as replicative immortality. This ability contrasts with the intrinsic control of the number of cell divisions in human somatic tissues by a mechanism called replicative senescence. Replicative immortality is acquired by inactivation of p53 and p16INK4a genes and reactivation of hTERT gene expression. It is unknown whether the cancer cell replicative immortality is reversible. Here, we show the spontaneous induction of replicative senescence in p53-and p16 INK4a-deficient hepatocellular carcinoma cells. This phenomenon is characterized with hTERT repression, telomere shortening, senescence arrest, and tumor suppression. SIP1 gene (ZFHX1B) is partly responsible for replicative senescence, because short hairpin RNA-mediated SIP1 inactivation released hTERT repression and rescued clonal hepatocellular carcinoma cells from senescence arrest. © 2006 by The National Academy of Sciences of the USA.