bluuebunny/crossref_metadata_2025_split huggingface dataset:
α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling
Authors: Inge Landon J. , Rajasekaran Sigrid A. , Wolle Daniel , Barwe Sonali P. , Ryazantsev Sergey , Ewing Charles M. , Isaacs William B. , Rajasekaran Ayyappan K. 
Published: June 2008

Abstract
Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α and β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In α-catenin-null prostate cancer cells, reexpression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin-null cells. α-Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy. [Mol Cancer Ther 2008;7(6):1386–97]
Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins
Authors: Zhai Dayong , Jin Chaofang , Shiau Chung-wai , Kitada Shinichi , Satterthwait Arnold C. , Reed John C. 
Published: June 2008

Abstract
The natural product gambogic acid (GA) has been reported to have cytotoxic activity against tumor cells in culture and was identified as an active compound in a cell-based high-throughput screening assay for activators of caspases, proteases involved in apoptosis. Using the antiapoptotic Bcl-2 family protein, Bfl-1, as a target for screening of a library of natural products, we identified GA as a competitive inhibitor that displaced BH3 peptides from Bfl-1 in a fluorescence polarization assay. Analysis of competition for BH3 peptide binding revealed that GA inhibits all six human Bcl-2 family proteins to various extents, with Mcl-1 and Bcl-B the most potently inhibited [concentrations required for 50% inhibition (IC50), &lt;1μmol/L]. Competition for BH3 peptide binding was also confirmed using a time-resolved fluorescence resonance energy transfer assay. GA functionally inhibited the antiapoptotic Bcl-2 family proteins as shown by experiments using isolated mitochondria in which recombinant purified Bcl-2 family proteins suppress SMAC release in vitro, showing that GA neutralizes their suppressive effects on mitochondria in a concentration-dependent manner. GA killed tumor cell lines via an apoptotic mechanism, whereas analogues of GA with greatly reduced potency at BH3 peptide displacement showed little or no cytotoxic activity. However, GA retained cytotoxic activity against bax−/−bak−/− cells in which antiapoptotic Bcl-2 family proteins lack a cytoprotective phenotype, implying that GA also has additional targets that contribute to its cytotoxic mechanism. Altogether, the findings suggest that suppression of antiapoptotic Bcl-2 family proteins may be among the cytotoxic mechanisms by which GA kills tumor cells. [Mol Cancer Ther 2008;7(6):1639–46]
Eps8 decreases chemosensitivity and affects survival of cervical cancer patients
Authors: Chen Yun-Ju , Shen Meng-Ru , Chen Yen-Jen , Maa Ming-Chei , Leu Tzeng-Horng 
Published: June 2008

Abstract
The oncoprotein Eps8 facilitates proliferation in fibroblasts and colon cancer cells. However, its role in human cervical cancer is unclear. By immunohistochemical staining and Western blotting, aberrant Eps8 expression was observed in cervical carcinoma compared with normal cervical epithelial cells. Clinicopathologic analysis of 45 patients indicated that Eps8 expression was associated with parametrium invasion and lymph node metastasis, two major poor prognostic factors for early-stage cervical cancer. Kaplan-Meier analysis of cervical cancer specimens also indicated an inverse relationship between the level of Eps8 and the patients' survival rate. Using small interfering RNA of eps8, we observed reduced proliferation and tumorigenesis in Eps8-attenuated HeLa and SiHa cells cultured in dishes or inoculated in mice. Furthermore, diminished Eps8 impeded G1-phase progression in HeLa and SiHa cells that might be attributable to reduced expression of cyclins D1, D3, and E, elevated accumulation of p53 and its downstream target p21Waf1/Cip1, and suppressed hyperphosphorylation of retinoblastoma. Alteration of these cell cycle–related proteins could be reversed by ectopic Eps8, implicating that the effect of Eps8 on the mentioned cell cycle modulators was specific. Notably, the augmented expression of p53 by diminished Eps8 was at least due to its decreased turnover rate. Concurrent with p53 up-regulation and the decrement of Src and AKT activity, Eps8-attenuated HeLa and SiHa cells exhibited increased chemosensitivity to cisplatin and paclitaxel. Together, our findings implicate the involvement of Eps8 in chemoresistance and show its importance in prognosis of cervical cancer patients. [Mol Cancer Ther 2008;7(6):1376–85]
Photodynamic therapy with an endocytically located photosensitizer cause a rapid activation of the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun NH2 terminal kinase with opposing effects on cell survival
Authors: Weyergang Anette , Kaalhus Olav , Berg Kristian 
Published: June 2008

Abstract
Photochemical internalization (PCI) is a method for release of endosomally/lysosomally trapped drugs into the cell cytosol. PCI is based on photosensitizers that accumulate in the membranes of endosomes and lysosomes. Light exposure generates reactive oxygen species that cause membrane rupture and subsequently drug release. PCI can be considered as a combination therapy of photodynamic therapy (PDT) and the administrated drug. The present work reports on mitogen-activated protein kinase signaling after PDT with the endocytically located photosensitizer TPPS2a (meso-tetraphenylporphine with two sulfonate groups on adjacent phenyl rings) as used for PCI in two cancer cell lines: NuTu-19 and WiDr. Both extracellular signal-regulated kinase (ERK) and p38 were activated immediately after PDT. The photochemically induced ERK phosphorylation was enhanced by epidermal growth factor stimulation to a level above that obtainable with epidermal growth factor alone. Expression of the ERK phosphatase, MAPK phosphatase-1, was increased 2 h after PDT but was not the cause of ERK dephosphorylation observed simultaneously. A transient activation of c-Jun NH2 terminal kinase was also observed after PDT but only in the NuTu-19 cells. Using suitable inhibitors, it is shown here that the p38 signal is a death signal, whereas c-Jun NH2 terminal kinase rescues cells after PDT. No direct connection was observed between PDT-induced ERK activation and toxicity of the treatment. The present results document the importance of the mitogen-activated protein kinases in TPPS2a-PDT-induced cytotoxicity. [Mol Cancer Ther 2008;7(6):1740–50]
KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling
Authors: Feng Rentian , Ma Huihui , Hassig Christian A. , Payne Joseph E. , Smith Nicholas D. , Mapara Markus Y. , Hager Jeffrey H. , Lentzsch Suzanne 
Published: June 2008

Abstract
Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138+ primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor–related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis. [Mol Cancer Ther 2008;7(6):1494–505]
Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes
Authors: Shkreta Lulzim , Froehlich Ulrike , Paquet Éric R. , Toutant Johanne , Elela Sherif Abou , Chabot Benoit 
Published: June 2008

Abstract
Inducing an apoptotic response is the goal of most current chemotherapeutic interventions against cancer. However, little is known about the effect of chemotherapeutic agents on the alternative splicing of apoptotic genes. Here, we have tested 20 of the mainstream anticancer drugs for their ability to influence the production of Bcl-x splice isoforms. We find that many drugs shift splicing toward the proapoptotic Bcl-xS splice variant in 293 cells. The drugs modulate splicing decisions most likely through signaling events because the splicing switch is not compromised by inhibiting de novo protein synthesis or the activity of caspases. Several drugs also shift Bcl-x splicing in cancer cell lines (MCF-7, HeLa, PC-3, PA-1, and SKOV-3), but the set of active drugs varies between cell lines. We also examined the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes in different cell lines. Almost every drug can alter a subset of alternative splicing events in each cell line. Although drugs of the same class often influence the alternative splicing of the same units in individual cell lines, these units differ considerably between cell lines, indicating cell line–specific differences in the pathways that control splicing. [Mol Cancer Ther 2008;7(6):1398–409]
Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo
Authors: Ning Shoucheng , Nemeth Jeffrey A. , Hanson Rebecca L. , Forsythe Kevin , Knox Susan J. 
Published: June 2008

Abstract
Selective targeting of up-regulated integrins on tumor cells is a novel antiangiogenesis strategy for treating solid tumors. CNTO 95 is a fully human anti-αv integrin monoclonal antibody and has shown antitumor activity when used as a single agent in preclinical studies. We previously showed that radiation combined with an integrin αvβ3 antagonist cRGD peptide increased the therapeutic efficacy of radiation in preclinical tumor models. We hypothesized that the combination of radiation and CNTO 95 would synergistically enhance the efficacy of radiation therapy. The in vitro studies showed that CNTO 95 radiosensitized and induced apoptosis in M21 cells in vitronectin-coated dishes. In mice bearing established human cancer xenograft tumors, CNTO 95 alone had only a moderate effect on tumor growth. The combined therapy of CNTO 95 and fractionated radiation significantly inhibited tumor growth and produced the longer tumor growth delay time in multiple tumor models. Maintenance dosing of CNTO 95 following irradiation contributed to efficacy and was important for continued inhibition of tumor regrowth. Immunohistochemistry studies showed that the combined use of CNTO 95 and radiation reduced the αv integrin and vascular endothelial growth factor receptor expression and the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. CNTO 95 alone and in combination with radiation did not produce any obvious signs of systemic toxicity. These results show that CNTO 95 can potentiate the efficacy of fractionated radiation therapy in a variety of human cancer xenograft tumor types in nude mice. These findings are very promising and may have high translational relevance for the treatment of patients with solid tumors. [Mol Cancer Ther 2008;7(6):1569–78]
Inhibition of Return in the Covert Deployment of Attention: Evidence from Human Electrophysiology
Authors: McDonald John J. , Hickey Clayton , Green Jessica J. , Whitman Jennifer C. 
Published: June 2008

Abstract
People are slow to react to objects that appear at recently attended locations. This delay—known as inhibition of return (IOR)—is believed to aid search of the visual environment by discouraging inspection of recently inspected objects. However, after two decades of research, there is no evidence that IOR reflects an inhibition in the covert deployment of attention. Here, observers participated in a modified visual-search task that enabled us to measure IOR and an ERP component called the posterior contralateral N2 (N2pc) that reflects the covert deployment of attention. The N2pc was smaller when a target appeared at a recently attended location than when it appeared at a recently unattended location. This reduction was due to modulation of neural processing in the visual cortex and the right parietal lobe. Importantly, there was no evidence for a delay in the N2pc. We conclude that in our task, the inhibitory processes underlying IOR reduce the probability of shifting attention to recently attended locations but do not delay the covert deployment of attention itself.
The Left Intraparietal Sulcus Modulates the Selection of Low Salient Stimuli
Authors: Mevorach Carmel , Shalev Lilach , Allen Harriet A. , Humphreys Glyn W. 
Published: June 2008

Abstract
Neuropsychological and functional imaging studies have suggested a general right hemisphere advantage for processing global visual information and a left hemisphere advantage for processing local information. In contrast, a recent transcranial magnetic stimulation study [Mevorach, C., Humphreys, G. W., & Shalev, L. Opposite biases in salience-based selection for the left and right posterior parietal cortex. Nature Neuroscience, 9, 740–742, 2006b] demonstrated that functional lateralization of selection in the parietal cortices on the basis of the relative salience of stimuli might provide an alternative explanation for previous results. In the present study, we applied a whole-brain analysis of the functional magnetic resonance signal when participants responded to either the local or the global levels of hierarchical figures. The task (respond to local or global) was crossed with the saliency of the target level (local salient, global salient) to provide, for the first time, a direct contrast between brain activation related to the stimulus level and that related to relative saliency. We found evidence for lateralization of salience-based selection but not for selection based on the level of processing. Activation along the left intraparietal sulcus (IPS) was found when a low saliency stimulus had to be selected irrespective of its level. A control task showed that this was not simply an effect of task difficulty. The data suggest a specific role for regions along the left IPS in salience-based selection, supporting the argument that previous reports of lateralized responses to local and global stimuli were contaminated by effects of saliency.
Effects of Psychostimulants on Alertness and Spatial Bias in Healthy Participants
Authors: Dodds Chris , Müller Ulrich , Manly Tom 
Published: June 2008

Abstract
Converging evidence from neuropsychological and neuroimaging studies suggests that the ability to maintain an alert, ready-to-respond state is mediated by a network of right-hemisphere frontal and parietal cortical areas. This right lateralization may help to explain why visuospatial hemineglect, a cluster of deficits in detecting and responding to contralesional stimuli, is more common and persistent after right-hemisphere lesions. Indeed, it has been hypothesized that this asymmetry reflects a direct, functional link between alertness and spatial attention. In the present study, we investigated whether a pharmacologically induced increase in alertness would influence lateral bias in healthy people. Eighteen healthy participants were each given placebo or the psychostimulant drugs methylphenidate 40 mg or modafinil 400 mg on separate days and completed an hour-long version of the spatially sensitive landmark task. For those participants who demonstrated the expected alerting effect of modafinil, there was a significant Condition by Time interaction, consistent with the effects of the drug resisting time-on-task rightward drifts in spatial bias in the placebo condition. In contrast, no effect of methylphenidate on spatial bias was observed. These results suggest that spatial bias may be modulated by a psychostimulant-induced increase in alertness, supporting the hypothesis of a direct, functional link between right-hemisphere systems controlling alertness and visuospatial attention.
Adult female wildtype, but not oestrogen receptor β knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile
Authors: Walf AA , Koonce CJ , Frye CA 
Published: June 2008

Abstract Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17β-oestradiol (E2), as well as administration of E2-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E2 is important to improve future E2-based therapeutics. An important question is whether effects of E2 or SERMs for mood regulation act at the α or β isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E2-based therapies may involve actions at ERα, rather than ERβ. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E2 (experiment 2), or administration of E2 or a SERM that has higher affinity for ERβ than for ERα (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERβ knockout (βERKO) mice were investigated. Results of this study supported our hypotheses that: there would be sex differences favouring males for depression-like behaviour and endogenous increases in, or exogenous administration of, E2 or administration of an ERβ SERM would decrease depression-like behaviour in wildtype, but not βERKO, mice. In experiment 1, adult male mice spent less time immobile in the forced swim test (i.e., showed less depression-like behaviour) compared with female mice. In experiment 2, pro-oestrous (higher circulating E2 levels), compared with dioestrous (lower circulating E2 levels), mice had reduced immobility in the forced swim test; this effect was not observed in βERKO mice. In experiment 3, administration of E2 or DPN to ovariectomised wildtype, but not βERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERβ may be required for some of the anti–depressant-like effects of E2.
The effect of clomipramine on wake/sleep and orexinergic expression in rats
Authors: Feng P , Hu Y , Li D , Vurbic D , Fan H , Wang S , Strohl KP 
Published: June 2008

AbstractWe have previously found that neonatal treatment with clomipramine (CLI) induced a decrease in brain orexins during the juvenile period and that these changes were reversed at adulthood. This study investigated the effect of CLI on the orexinergic component and sleep/wake states. Two groups of adult male rats were conducted for 48-h polysomnographic recording. One group of rats was treated with CLI (20 mg/kg every 12 h), and a second group was treated with equivolume of saline (SAL) simultaneously after the first 24 h of polysomnographic recording. Rats were killed 2 h after the third dose of treatment. Brain tissues were collected for radioimmunoassay quantification of orexins and real-time PCR analysis of prepro-orexin and orexin receptor mRNA. The CLI group had significantly shorter rapid eye movement (REM) sleep and longer REM latency compared with both the baseline day and the SAL group and had significantly less active wake and more quiet wake. Compared with the control rats, the CLI rats had significantly higher mRNA expression of prepro-orexin in the hypothalamus and the frontal cortex, but not in the hippocampus. The CLI rats also had significantly less orexin B in the hypothalamus than the control rats. These results suggest that suppression of active wake and orexin B by CLI may be a factor responsible for CLI-induced depression and that the increase of prepro-orexin mRNA may be a sign of increased brain orexins found in this model.
Behavioural signs of depression and apoptosis in the limbic system following myocardial infarction: effects of sertraline
Authors: Wann BP , Bah TM , Kaloustian S , Boucher M , Dufort AM , Le Marec N , Godbout R , Rousseau G 
Published: June 2008

Abstract Depression is diagnosed in 15–30% of patients following myocardial infarction (MI) and this may also be observed in the rat. We measured the effects of the antidepressant sertraline on behavioural and biochemical events following MI in a rat model. Following surgery, MI rats and sham controls were treated with sertraline (10 mg/kg, i.p.) or saline. Subgroups of rats were tested for behavioural depression 14 days after surgery. Apoptosis was estimated in other rats by measuring caspase-3 activity and TUNEL positive cells (3 days after surgery) in limbic structures (amygdale, hippocampus, hypothalamus, frontal and prefrontal cortices). Bax/Bcl-2 ratio was measured 14 days after surgery. Behavioural signs of depression (decreased sucrose intake and forced swimming time) were found in saline-treated MI rats but not in sertraline-treated rats. Compared with controls, caspase-3 activity and TUNEL positive cells were significantly increased in most limbic structures of MI rats. High prefrontal Bax/Bcl-2 ratio in MI rats correlated with low forced swimming time. Apoptosis was not found in sertraline-treated MI rats. These results establish the bases of a rat model of depression following MI and show for the first time that a selective serotonin reuptake inhibitor prevents both behavioural and biochemical markers in this model.