bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipid rafts remodeling in estrogen receptor–negative breast cancer is reversed by histone deacetylase inhibitor
Authors: Ostapkowicz Anna , Inai Kunihiro , Smith Leia , Kreda Silvia , Spychala Jozef 
Published: March 2006

Abstract
Recently, we have found dramatic overexpression of ecto-5′-nucleotidase (or CD73), a glycosylphosphatidylinositol-anchored component of lipid rafts, in estrogen receptor–negative [ER(−)] breast cancer cell lines and in clinical samples. To find out whether there is a more general shift in expression profile of membrane proteins, we undertook an investigation on the expression of selected membrane and cytoskeletal proteins in aggressive and metastatic breast cancer cells. Our analysis revealed a remarkably uniform shift in expression of a broad range of membrane, cytoskeletal, and signaling proteins in ER(−) cells. A similar change was found in two in vitro models of transition to ER(−) breast cancer: drug-resistant Adr2 and c-Jun-transformed clones of MCF-7 cells. Interestingly, similar expression pattern was observed in normal fibroblasts, suggesting the commonality of membrane determinants of invasive cancer cells with normal mesenchymal phenotype. Because a number of investigated proteins are components of lipid rafts, our results suggest that there is a major remodeling of lipid rafts and underlying cytoskeleton in ER(−) breast cancer. To test whether this broadly defined ER(−) phenotype could be reversed by treatment with differentiating agent, we treated ER(−) cells with trichostatin A, an inhibitor of histone deacetylase, and observed reversal of mesenchymal and reappearance of epithelial markers. Changes in gene and protein expression also included increased capacity to generate adenosine and altered expression profile of adenosine receptors. Thus, our results suggest that during transition to invasive breast cancer there is a significant structural reorganization of lipid rafts and underlying cytoskeleton that is reversed upon histone deacetylase inhibition. [Mol Cancer Ther 2006;5(2):238–45]
The inverse relationship between reduced folate carrier function and Pemetrexed activity in a human colon cancer cell line
Authors: Chattopadhyay Shrikanta , Zhao Rongbao , Krupenko Sergey A. , Krupenko Natalia , Goldman I. David 
Published: March 2006

AbstractPemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non–small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced (∼85%) but intracellular pemetrexed levels increased to ∼60% and ∼70% to that of wild-type cells after 2 hours and 6 days, respectively. There was increased pemetrexed inhibition of glycinamide ribonucleotide transformylase and, to a lesser extent, thymidylate synthase in PT1 cells growing in 5-formyltetrahydrofolate based on nucleoside protection analyses. Hence, loss of RFC function leads to collateral sensitivity to pemetrexed in HCT-15 cells, likely due to cellular folate pool contraction resulting in partial preservation of pemetrexed polyglutamylation and increased target enzyme inhibition. [Mol Cancer Ther 2006;5(2):438–49]
Class III β-tubulin expression in tumor cells predicts response and outcome in patients with non–small cell lung cancer receiving paclitaxel
Authors: Sève Pascal , Mackey John , Isaac Sylvie , Trédan Olivier , Souquet Pierre-Jean , Pérol Maurice , Lai Raymond , Voloch Alain , Dumontet Charles 
Published: March 2006

AbstractBoth fundamental and clinical studies suggest that class III β-tubulin expression is associated with resistance to taxanes and constitutes a prognostic factor in several solid tumors. In this study, we assessed the prognostic and predictive value of class III β-tubulin in tumors of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) treated with paclitaxel-based or other regimens that did not include tubulin-binding agents. Expression of class III β-tubulin was examined immunohistochemically in 91 tumor samples obtained before treatment from patients with stage III and IV NSCLC, including 47 who received paclitaxel-based regimens and 44 who received regimens without tubulin-binding agents. Response to chemotherapy, progression-free survival, and overall survival were correlated with the expression of class III β-tubulin protein. The response rate was 37.5% (16 responses among 45 evaluable patients) among patients receiving paclitaxel. Patients whose tumors expressed low levels of class III β-tubulin isotype had a better response rate, longer progression-free survival, and overall survival (P &lt; 0.001, 0.004, and 0.002, respectively), whereas this variable was not found to be predictive in patients receiving regimens without tubulin-binding agents. A multivariate analysis taking into account sex, age, histology, stage, and class III β-tubulin confirmed that low-level class III β-tubulin expression was independently correlated with progression-free survival (P = 0.003) and overall survival (P = 0.003). These findings suggest that the expression levels of class III β-tubulin in tumor cells is predictive of response to therapy and patient outcome in patients with NSCLC receiving paclitaxel-based chemotherapy but is not a general prognostic factor in this patient population. [Mol Cancer Ther 2005;4(12):2001–7]
Novel missense mutation of the DNA topoisomerase I gene in SN-38-resistant DLD-1 cells
Authors: Arakawa Yasuhiro , Suzuki Hideaki , Saito Shinobu , Yamada Hisashi 
Published: March 2006

AbstractIrinotecan hydrochloride, a camptothecin derivative, is one of the most effective drugs for colorectal cancer, and SN-38 is its main active metabolite. Development of resistance is a major obstacle to the clinical application of this drug. We established an SN-38-resistant subline from DLD-1 human colon cancer cells by continuous exposure to SN-38 and studied the mechanisms of resistance. The resistant subline (designated as DLDSNR6) had 10- to 100-fold higher resistance to camptothecin derivatives but showed no cross-resistance to doxorubicin, mitomycin C, and etoposide. DLDSNR6 cells carried a missense mutation in one allele of the DNA topoisomerase I gene that substituted glycine for serine at amino acid residue 365 accompanied by loss of the latter part of the remaining wild-type allele. Topoisomerase I expression was equal in DLDSNR6 and DLD-1 cells, but the nuclear extract of DLDSNR6 cells showed lower topoisomerase I catalytic activity. Moreover, exposure to camptothecin caused less accumulation of topoisomerase I-DNA complexes in DLDSNR6 cells than in DLD-1 cells. These findings suggest that the mutation interfered with both the catalytic activity of topoisomerase I and the stability of the ternary complex between topoisomerase I, DNA, and SN-38. This SN-38-resistant DLDSNR6 cell line may be useful for understanding the mechanisms of topoisomerase I function and drug-enzyme interactions. [Mol Cancer Ther 2006;5(3):502–8]
Guggulsterones induce apoptosis and differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the pregnadienedione structure
Authors: Samudio Ismael , Konopleva Marina , Safe Stephen , McQueen Teresa , Andreeff Michael 
Published: March 2006

Abstract
In this study, the antileukemic effects of three isomeric pregnadienedione steroids [i.e., cis-guggulsterone, trans-guggulsterone, and 16-dehydroprogesterone] were investigated in HL60 and U937 cells as well as in primary leukemic blasts in culture. Our results show that all three compounds inhibited the proliferation of HL60 and U937 cells, with IC50s ranging from 3.6 to 10.9 μmol/L after treatment for 6 days. These growth inhibitory effects correlated with externalization of phosphatidylserine and loss of mitochondrial membrane potential, suggesting that these isomeric steroids induce apoptosis in leukemia cells. z-VAD-fmk prevented phosphatidylserine externalization but not mitochondrial membrane potential loss, indicating that mitochondrial dysfunction occurred in the absence of caspase activation. Interestingly, although all three compounds increased the generation of reactive oxygen species and decreased phosphorylation of extracellular signal-regulated kinase, only cis-guggulsterone induced a rapid depletion of reduced glutathione levels and oxidation of the mitochondrial phospholipid cardiolipin. 16-Dehydroprogesterone and trans-guggulsterone induced differentiation of HL60 and NB4 cells as evidenced by increased surface expression of CD11b and/or CD14, and all three steroids rapidly induced mitochondrial dysfunction and phosphatidylserine externalization of CD34-positive blasts from primary leukemic samples. This study is the first to show that guggulsterones and 16-dehydroprogesterone exert antileukemic effects via the induction of apoptosis and differentiation and, more importantly, identifies the pregnadienedione structure as a potential chemotherapeutic scaffold. [Mol Cancer Ther 2005;4(12):1982–92]
Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function
Authors: Feng Yang , Zhu Zhongyu , Xiao Xiaodong , Choudhry Vidita , Barrett J. Carl , Dimitrov Dimiter S. 
Published: March 2006

AbstractThe insulin-like growth factor (IGF) system plays an important role in a variety of physiologic processes and in diseases such as cancer. Although the role of the IGF system in cancer has been recognized many years ago, components of the system have only recently been targeted and shown to affect cell transformation, proliferation, survival, motility, and migration in tissue cultures and in mouse models of cancer. We have been hypothesizing that targeting IGF-II in addition to blocking its interaction with the IGF receptor type I (IGF-IR) would also allow to block that portion of the signal transduction through the insulin receptor that is due to its interaction with IGF-II. Lowering its level may also not induce up-regulation of its production as for IGF-I. Finally, targeting a diffusable ligand as IGF-II may not require penetration of the antibody inside tumors but could shift the equilibrium to IGF-II complexed with antibody so the ligand concentration would decrease in the tumor environment without the need for the antibody to penetrate the tumor. Here, we describe the identification and characterization of three novel anti-IGF-II fully human monoclonal antibodies. They bound with high (subnanomolar) affinity to IGF-II, did not cross-react with IGF-I and insulin, and potently inhibited signal transduction mediated by the IGF-IR interaction with IGF-II. The most potent neutralizer, IgG1 m610, inhibited phosphorylation of the IGF-IR and the insulin receptor, as well as phosphorylation of the downstream kinases Akt and mitogen-activated protein kinase with an IC50 of the order of 1 nmol/L at IGF-II concentration of 10 nmol/L. It also inhibited growth of the prostate cancer cell line DU145 and migration of the breast cancer line cells MCF-7. These results indicate an immunotherapeutic potential of IgG1 m610 likely in combination with other antibodies and anticancer drugs but only further experiments in mouse models of cancer and human clinical trials could evaluate this possibility. [Mol Cancer Ther 2006;5(1):114–20]
Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP
Authors: Galligan Leeona , Longley Daniel B. , McEwan Miranda , Wilson Timothy R. , McLaughlin Kirsty , Johnston Patrick G. 
Published: March 2006

AbstractTumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain–like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL–induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies. [Mol Cancer Ther 2005;4(12):2026–36]
Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery
Authors: Wang Yong , Wang He , Li Chuan-Yuan , Yuan Fan 
Published: March 2006

Abstract
Recent studies have shown that up to 90% of viral vectors could disseminate to normal organs following intratumoral infusion. The amount of dissemination might be dependent on the infusion conditions. Therefore, we investigated the effects of infusion rate, volume, and dose on transgene expression in liver and tumor tissues after intratumoral infusion of an adenoviral vector encoding luciferase. Luciferase expression was determined through bioluminescence intensity measurement. We observed that the luciferase expression in the liver was independent of the infusion rate but increased with the infusion dose, whereas the luciferase expression in the tumor was a bell-shaped function of the infusion rate. The latter observation was consistent with the distribution pattern of Evans blue–labeled albumin after its solution was infused into tumors at the same infusion rates. We also observed that the infusion volume could affect luciferase expression in the tumor but not in the liver. These observations implied that virus dissemination was determined mainly by the infusion dose, whereas the amount of transgene expression in the tumor depended on the distribution volume of viral vectors in the tumor as well as the infusion dose. [Mol Cancer Ther 2006;5(2):362–6]
Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein
Authors: Kotha Anupama , Sekharam Madhavi , Cilenti Lucia , Siddiquee Khandaker , Khaled Annette , Zervos Antonis S. , Carter Bradford , Turkson James , Jove Richard 
Published: March 2006

Abstract
Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (Stat3) protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active Stat3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G0-G1 phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant Stat3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated Stat3 profile. [Mol Cancer Ther 2006;5(3):621–9]
A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases
Authors: Zhou Bingsen , Shao Jimin , Su Leila , Yuan Yate-Ching , Qi Christina , Shih Jennifer , Xi Bixin , Chu Bernard , Yen Yun 
Published: March 2006

Abstract
Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity. Mutations of this newly identified tyrosine residue obliterated the stable radical and the enzymatic activity of human ribonucleotide reductases shown by electron paramagnetic resonance spectroscopy and enzyme activity assays. Three-dimensional structural analysis reveals for the first time that these two tyrosines are located at opposite sides of the diiron cluster. We conclude that both tyrosines are necessary in maintaining the diiron cluster of the enzymes, suggesting that the assembly of a dityrosyl-diiron radical cofactor center in human ribonucleotide reductases is essential for enzyme catalytic activity. These results should provide insights to design better ribonucleotide reductase inhibitors for cancer therapy. [Mol Cancer Ther 2005;4(12):1830–6]
SUMOylation plays a role in gemcitabine- and bortezomib-induced cytotoxicity in human oropharyngeal carcinoma KB gemcitabine-resistant clone
Authors: Chung Vincent , Zhou Bingsen , Liu Xiyong , Zhu Lijun , Boo Lee M. , Nguyen Ha-Van , Ann David K. , Song Jing , Chen Yuan , Yen Yun 
Published: March 2006

Abstract
Bortezomib, a novel dipeptide boronic acid proteasome inhibitor, has been shown in previous studies to be synergistic with gemcitabine; however, the molecular mechanisms are not fully understood. Because post-translational modification of proteins, such as ubiquitination and SUMOylation, plays a critical role in governing cellular homeostasis, we explored this further by treating human oropharyngeal carcinoma KB wild-type (KBwt) and gemcitabine-resistant (KBGem) cells with gemcitabine and bortezomib in a time-dependent and sequence-dependent manner. Treatment with bortezomib at 4 to 8 hours post-gemcitabine significantly induced cell death in KBwt cell lines. However, in KBGem cells, bortezomib alone was just as cytotoxic. Using reporter assays, nuclear factor-κB (NF-κB) activity was found to be 5-fold higher in KBGem cells than that in KBwt cells, and the combination treatment decreased NF-κB activity by 44% in KBwt cells and 28% in KBGem cells, respectively. By Western blot analyses, treatment with gemcitabine and bortezomib resulted in a cleavage of NF-κB in KBwt but not in KBGem cells. SUMOylation capacity was modulated by transducing KBwt and KBGem cells with lenti-SUMO-1 or the unconjugatable lenti-SUMO-1aa followed by drug treatment. The expression of cyclins A, D1, and E was differentially regulated by SUMOylation capacity in KBGem but not in KBwt cells. We report herein that the activation of NF-κB signaling plays a critical role in eliciting KBwt cell survival against gemcitabine, whereas the role of SUMOylation in modulating the steady-state levels of key cell cycle regulator proteins seems more significant in KBGem cells. [Mol Cancer Ther 2006;5(3):533–40]
Modulation of nuclear factor E2-related factor 2–mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin
Authors: Shen Guoxiang , Xu Changjiang , Hu Rong , Jain Mohit R. , Gopalkrishnan Avantika , Nair Sujit , Huang Mou-Tuan , Chan Jefferson Y. , Kong Ah-Ng Tony 
Published: March 2006

AbstractCurcumin has been shown to prevent and inhibit carcinogen-induced tumorigenesis in different organs of rodent carcinogenesis models. Our objective is to study global gene expression profiles elicited by curcumin in mouse liver and small intestine as well as to identify curcumin-regulated nuclear factor E2-related factor 2 (Nrf2)–dependent genes. Wild-type C57BL/6J and Nrf2 knockout C57BL/6J/Nrf2(−/−) mice were given a single oral dose of curcumin at 1,000 mg/kg. Liver and small intestine were collected at 3 and 12 hours after treatments. Total RNA was extracted and analyzed using Affymetrix (Santa Clara, CA) mouse genome 430 array (45K) and GeneSpring 6.1 software (Silicon Genetics, Redwood City, CA). Genes that were induced or suppressed &gt;2-fold by curcumin treatments compared with vehicle in wild-type mice but not in knockout mice were filtered using GeneSpring software and regarded as Nrf2-dependent genes. Among those well-defined genes, 822 (664 induced and 158 suppressed) and 222 (154 induced and 68 suppressed) were curcumin-regulated Nrf2-dependent genes identified in the liver and small intestine, respectively. Based on their biological functions, these genes can be classified into the category of ubiquitination and proteolysis, electron transport, detoxification, transport, apoptosis and cell cycle control, cell adhesion, kinase and phosphatase, and transcription factor. Many phase II detoxification/antioxidant enzyme genes, which are regulated by Nrf2, are among the identified genes. The identification of curcumin-regulated Nrf2-dependent genes not only provides potential novel insights into the biological effects of curcumin on global gene expression and chemoprevention but also points to the potential role of Nrf2 in these processes. [Mol Cancer Ther 2006;5(1):39–51]