bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor and Antimetastatic Activities of Docetaxel Are Enhanced by Genistein through Regulation of Osteoprotegerin/Receptor Activator of Nuclear Factor-κB (RANK)/RANK Ligand/MMP-9 Signaling in Prostate Cancer
Authors: Li Yiwei , Kucuk Omer , Hussain Maha , Abrams Judith , Cher Michael L. , Sarkar Fazlul H. 
Published: May 2006

Abstract
Bone metastasis is very common in advanced prostate cancer. Docetaxel has been shown to improve survival in patients with metastatic prostate cancer. However, treatment with docetaxel is associated with a certain degree of toxicity. Genistein, derived from soybeans, has been found to inhibit cancer cell growth without toxicity. We have recently reported that genistein could potentiate the antitumor activity of chemotherapeutic agents both in vitro and in vivo. However, the molecular mechanism of this novel effect of genistein has not been fully elucidated. In this study, we found that genistein significantly potentiated the antitumor, anti-invasive, and antimetastatic activities of docetaxel both in culture and in severe combined immunodeficient (SCID)-human model of experimental prostate cancer bone metastasis. We further conducted microarray analysis, real-time reverse transcription-PCR, Western blot analysis, small interfering RNA and cDNA transfection, matrix metalloproteinase-9 (MMP-9) activity assay, and invasion assay. We found that the expression of osteoprotegerin (OPG) was induced by genistein and inhibited by docetaxel, whereas genistein significantly down-regulated the expression and secretion of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and inhibited osteoclast formation. Moreover, genistein down-regulated the expression and activity of MMP-9, which was induced by docetaxel treatment, and inhibited invasion of PC-3 cells. These results suggest that the observed potentiation of antitumor activity of docetaxel by genistein in the SCID-human model of experimental bone metastasis could be mediated by regulation of OPG/RANK/RANKL/MMP-9 signaling, resulting in the inhibition of osteoclastic bone resorption and prostate cancer bone metastasis. From these results, we conclude that genistein could be a promising nontoxic agent to improve the treatment outcome of metastatic prostate cancer with docetaxel. (Cancer Res 2006; 66(9): 4816-25)
DNA Sequence Context Affects Repair of the Tobacco-Specific Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by Human O6-Alkylguanine-DNA Alkyltransferases
Authors: Mijal Renée S. , Kanugula Sreenivas , Vu Choua C. , Fang Qingming , Pegg Anthony E. , Peterson Lisa A. 
Published: May 2006

Abstract
The repair protein O6-alkylguanine-DNA alkyltransferase (AGT) protects cells from the mutagenic and carcinogenic effects of alkylating agents by removing O6-alkylguanine adducts from DNA. Recently, we established that AGT protects against the mutagenic effects of pyridyloxobutylation resulting from the metabolic activation of the tobacco-specific nitrosamines (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosonornicotine by repairing O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG). There have been several epidemiologic studies examining the association between the I143V/K178R AGT genotype and lung cancer risk. Two studies have found positive associations, suggesting that AGT proteins differ in their repair of DNA damage caused by TSNA. However, it is not known how this genotype alters the biochemical activity of AGT. We proposed that AGT proteins may differ in their ability to remove large O6-alkylguanine adducts, such as O6-pobG, from DNA. Therefore, we examined the repair of O6-pobG by wild-type (WT) human, I143V/K178R, and L84F AGT proteins when contained in multiple sequence contexts, including the twelfth codon of H-ras, a mutational hotspot within this oncogene. The AGT-mediated repair of O6-pobG was more profoundly influenced by sequence context than that of O6-methylguanine. These differences are not the result of secondary structure (hairpin) formation in DNA. In addition, the I143V/K178R variant seems less sensitive to the effects of sequence context than the WT or L84F proteins. These studies indicate that the sequence dependence of O6-pobG repair by human AGT (hAGT) varies with subtle changes in protein structure. These data establish a novel functional difference between the I143V/K178R protein and other hAGTs in the repair of a toxicologically relevant substrate, O6-pobG. (Cancer Res 2006; 66(9): 4968-74)
Reversible Kinetic Analysis of Myc Targets In vivo Provides Novel Insights into Myc-Mediated Tumorigenesis
Authors: Lawlor Elizabeth R. , Soucek Laura , Brown-Swigart Lamorna , Shchors Ksenya , Bialucha C. Uli , Evan Gerard I. 
Published: May 2006

Abstract
Deregulated expression of the Myc transcription factor is a frequent causal mutation in human cancer. Thousands of putative Myc target genes have been identified in in vitro studies, indicating that Myc exerts highly pleiotropic effects within cells and tissues. However, the complexity and diversity of Myc gene targets has confounded attempts at identifying which of these genes are the critical targets mediating Myc-driven tumorigenesis in vivo. Acute activation of Myc in a reversibly switchable transgenic model of Myc-mediated β cell tumorigenesis induces rapid tumor onset, whereas subsequent Myc deactivation triggers equally rapid tumor regression. Thus, sustained Myc activity is required for tumor maintenance. We have used this reversibly switchable kinetic tumor model in combination with high-density oligonucleotide microarrays to develop an unbiased strategy for identifying candidate Myc-regulated genes responsible for maintenance of Myc-dependent tumors. Consistent with known Myc functions, some Myc-regulated genes are involved in cell growth, cycle, and proliferation. In addition, however, many Myc-regulated genes are specific to β cells, indicating that a significant component of Myc action is cell type specific. Finally, we identify a very restricted cadre of genes with expression that is inversely regulated upon Myc activation-induced tumor progression and deactivation-induced tumor regression. By definition, such genes are candidates for tumor maintenance functions. Combining reversibly switchable, transgenic models of tumor formation and regression with genomic profiling offers a novel strategy with which to deconvolute the complexities of oncogenic signaling pathways in vivo. (Cancer Res 2006; 66(9): 4591-601)
Survival Signaling by Notch1: Mammalian Target of Rapamycin (mTOR)–Dependent Inhibition of p53
Authors: Mungamuri Sathish Kumar , Yang XiaoHe , Thor Ann D. , Somasundaram Kumaravel 
Published: May 2006

AbstractNotch signaling is believed to promote cell survival in general. However, the mechanism is not clearly understood. Here, we show that cells expressing intracellular domain of human Notch1 (NIC-1) are chemoresistant in a wild-type p53-dependent manner. NIC-1 inhibited p53 by inhibiting its activating phosphorylations at Ser15, Ser20, and Ser392 as well as nuclear localization. In addition, we found that inhibition of p53 by NIC-1 mainly occurs through mammalian target of rapamycin (mTOR) using phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway as the mTOR inhibitor, rapamycin treatment abrogated NIC-1 inhibition of p53 and reversed the chemoresistance. Consistent with this, rapamycin failed to reverse NIC-1-induced chemoresistance in cells expressing rapamycin-resistant mTOR. Further, ectopic expression of eukaryotic initiation factor 4E (eIF4E), a translational regulator that acts downstream of mTOR, inhibited p53-induced apoptosis and conferred protection against p53-mediated cytotoxicity to similar extent as that of NIC-1 overexpression but was not reversed by rapamycin, which indicates that eIF4E is the major target of mTOR in Notch1-mediated survival signaling. Finally, we show that MCF7 (breast cancer) and MOLT4 (T-cell acute lymphoblastic leukemia) cells having aberrant Notch1 signaling are chemoresistant, which can be reversed by both PI3K and mTOR inhibitors. These results establish that Notch1 signaling confers chemoresistance by inhibiting p53 pathway through mTOR-dependent PI3K-Akt/PKB pathway and imply that p53 status perhaps is an important determinant in combination therapeutic strategies, which use mTOR inhibitors and chemotherapy. (Cancer Res 2006; 66(9): 4715-24)
Identification of a New Cancer/Germline Gene,KK-LC-1, Encoding an Antigen Recognized by Autologous CTL Induced on Human Lung Adenocarcinoma
Authors: Fukuyama Takashi , Hanagiri Takeshi , Takenoyama Mitsuhiro , Ichiki Yoshinobu , Mizukami Makiko , So Tetsuya , Sugaya Masakazu , So Tomoko , Sugio Kenji , Yasumoto Kosei 
Published: May 2006

AbstractThe purpose of our present study is to identify a tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. We established a lung adenocarcinoma cell line, designated as F1121L, and induced tumor-specific CTL clone H1 from regional lymph node lymphocytes of patient F1121. CTL clone H1 lysed autologous tumor cells in an HLA-B*1507-restricted manner, but not autologous EBV-B, phytohemagglutinin-blast cells, and K562. The CTL clone also recognized allogeneic HLA-B*1501- or 1507-positive lung cancer cell lines in the HLA-restricted manner. Using the CTL clone, we identified an antigen-coding gene by cDNA expression cloning technique. The gene consisted of 556 bp, including an open reading frame consisted of 113 amino acids, designated as Kita-kyushu lung cancer antigen 1 (KK-LC-1). A 9-mer peptide (KK-LC-176-84; RQKRILVNL) was identified as an epitope peptide. The genomic DNA of this antigen was located in chromosome Xq22. A reverse transcription-PCR analysis revealed that the mRNA of this gene was only expressed in the testis among normal tissues. It was expressed in 9 of 18 (50%) allogeneic non–small-cell lung cancer cell lines and in 40 of 100 (40%) non–small-cell lung cancer tissues. We thus identified a new tumor antigen–coding gene categorized as a cancer/germline gene by an autologous lung cancer and CTL system. The new cancer/germline gene was located in Xq22, which is apparently different from the locations of previously reported cancer/germline genes. (Cancer Res 2006; 66(9): 4922-8)
Exploring a New Twist on Tumor Metastasis
Authors: Yang Jing , Mani Sendurai A. , Weinberg Robert A. 
Published: May 2006

Abstract
Unraveling the genetic programs that drive -metastasis may offer insights into how to limit or prevent this deadly aspect of cancer progression. Our recent studies indicate that tumor cell metastasis involves the activity of the transcription factor, Twist, which regulates epithelial-mesenchymal transition and early embryonic morphogenesis. Here, we review the Twist signaling pathway during normal development and discuss how the transcription factor Twist and the epithelial-mesenchymal transition program impinge their biological functions during tumor metastasis. (Cancer Res 2006; 66(9): 4549-52)
Normal Stem Cells and Cancer Stem Cells: The Niche Matters
Authors: Li Linheng , Neaves William B. 
Published: May 2006

Abstract
Scientists have tried for decades to understand cancer development in the context of therapeutic strategies. The realization that cancers may rely on “cancer stem cells” that share the self-renewal feature of normal stem cells has changed the perspective with regard to new approaches for treating the disease. In this review, we propose that one of the differences between normal stem cells and cancer stem cells is their degree of dependence on the stem cell niche, a specialized microenvironment in which stem cells reside. The stem cell niche in adult somatic tissues plays an essential role in maintaining stem cells or preventing tumorigenesis by providing primarily inhibitory signals for both proliferation and differentiation. However, the niche also provides transient signals for stem cell division to support ongoing tissue regeneration. The balance between proliferation-inhibiting and proliferation-promoting signals is the key to homeostatic regulation of stem cell maintenance versus tissue regeneration. Loss of the niche can lead to loss of stem cells, indicating the reliance of stem cells on niche signals. Therefore, cancer stem cells may arise from an intrinsic mutation, leading to self-sufficient cell proliferation, and/or may also involve deregulation or alteration of the niche by dominant proliferation-promoting signals. Furthermore, the molecular machinery used by normal stem cells for homing to or mobilizing from the niche may be “hijacked” by cancer stem cells for invasion and metastasis. We hope this examination of the interaction between stem cells and their niche will enhance understanding of the process of cancer development, invasiveness, and metastasis and reveal possible targets for cancer treatment. (Cancer Res 2006; 66(9): 4553-7)
Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids
Authors: Selvendiran Karuppaiyah , Koga Hironori , Ueno Takato , Yoshida Takafumi , Maeyama Michiko , Torimura Takuji , Yano Hirohisa , Kojiro Masamichi , Sata Michio 
Published: May 2006

Abstract
In this study, we have investigated the underlying molecular mechanism for the potent proapoptotic effect of luteolin on human hepatoma cells both in vitro and in vivo, focusing on the signal transducer and activator of transcription 3 (STAT3)/Fas signaling. A clear apoptosis was found in the luteolin-treated HLF hepatoma cells in a time- and dosage-dependent manner. In concert with the caspase-8 activation by luteolin, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr705 phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was found within 20 minutes in the luteolin-treated cells, leading to down-regulation in the target gene products of STAT3, such as cyclin D1, survivin, Bcl-xL, and vascular endothelial growth factor. Of interest, the rapid down-regulation in STAT3 was consistent with an accelerated ubiquitin-dependent degradation in the Tyr705-phosphorylated STAT3, but not the Ser727-phosphorylated one, another regulator of STAT3 activity. The expression level of Ser727-phosphorylated STAT3 was gradually decreased by the luteolin treatment, followed by a fast and clear down-regulation in the active forms of CDK5, which can phosphorylate STAT3 at Ser727. An overexpression in STAT3 led to resistance to luteolin, suggesting that STAT3 was a critical target of luteolin. In nude mice with xenografted tumors using HAK-1B hepatoma cells, luteolin significantly inhibited the growth of the tumors in a dosage-dependent manner. These data suggested that luteolin targeted STAT3 through dual pathways—the ubiquitin-dependent degradation in Tyr705-phosphorylated STAT3 and the gradual down-regulation in Ser727-phosphorylated STAT3 through inactivation of CDK5, thereby triggering apoptosis via up-regulation in Fas/CD95. (Cancer Res 2006; 66(9): 4826-34)
Molecular Evidence for Independent Origin of Multifocal Neuroendocrine Tumors of the Enteropancreatic Axis
Authors: Katona Terrence M. , Jones Timothy D. , Wang Mingsheng , Abdul-Karim Fadi W. , Cummings Oscar W. , Cheng Liang 
Published: May 2006

Abstract
Neuroendocrine tumors of the enteropancreatic axis are often multifocal. We have investigated whether multifocal intestinal carcinoid tumors and multifocal pancreatic endocrine tumors arise independently or whether they originate from a single clone with subsequent intramural or intrapancreatic spread. Twenty-four cases, including 16 multifocal intestinal carcinoid tumors and eight multifocal pancreatic endocrine tumors, were studied. Genomic DNA samples were prepared from 72 distinct tumor nodules using laser capture microdissection. Loss of heterozygosity (LOH) assays were done using markers for putative tumor suppressor genes located on chromosomes 9p21 (p16), 11q13 (MEN1), 11q23 (SDHD), 16q21, 18q21, and 18q22-23. In addition, X chromosome inactivation analysis was done on the tumors from eight female patients. Twenty-two of 24 (92%) cases showed allelic loss in at least one tumor focus, including 15 of 16 (94%) cases of multifocal carcinoid tumors and 7 of 8 (88%) cases of multifocal pancreatic endocrine tumors. Eleven of 24 (46%) cases exhibited a different LOH pattern for each tumor. Additionally, 9 of 24 (38%) cases showed different LOH patterns among some of the coexisting tumors, whereas other coexisting tumors displayed the same allelic loss pattern. Two of 24 (8%) cases showed the same LOH pattern in every individual tumor. X chromosome inactivation analysis showed a discordant pattern of nonrandom X chromosome inactivation in two of six informative cases and concordant pattern of nonrandom X chromosome inactivation in the four remaining informative cases. Our data suggest that some multifocal neuroendocrine tumors of the enteropancreatic axis arise independently, whereas others originate as a single clone with subsequent local and discontinuous metastasis. (Cancer Res 2006; 66(9): 4936-42)
Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas
Authors: Onken Michael D. , Ehlers Justis P. , Worley Lori A. , Makita Jun , Yokota Yoshifumi , Harbour J. William 
Published: May 2006

Abstract
Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metastatic death. Class 1 tumors have a low risk and class 2 tumors a high risk for metastatic death. Here, we used genes that discriminate these tumor classes to identify biological correlates of the aggressive class 2 signature. A search for Gene Ontology categories enriched in our class-discriminating gene list revealed a global down-regulation of neural crest and melanocyte-specific genes and an up-regulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up-regulation of the epithelial adhesion molecule E-cadherin, colocalization of E-cadherin and β-catenin to the plasma membrane, and formation of cell-cell adhesions and acinar structures. One of our top class-discriminating genes was the helix-loop-helix inhibitor ID2, which was strongly down-regulated in class 2 tumors. The class 2 phenotype could be recapitulated by eliminating Id2 in cultured class 1 human uveal melanoma cells and in a mouse ocular melanoma model. Id2 seemed to suppress the epithelial-like class 2 phenotype by inhibiting an activator of the E-cadherin promoter. Consequently, Id2 loss triggered up-regulation of E-cadherin, which in turn promoted anchorage-independent cell growth, a likely antecedent to metastasis. These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention. (Cancer Res 2006; 66(9): 4602-9)
The Role of Mitogen-Activated Protein Kinase Phosphatase-1 in Oxidative Damage–Induced Cell Death
Authors: Zhou Jun-Ying , Liu Yusen , Wu Gen Sheng 
Published: May 2006

Abstract
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a member of the MAPK phosphatase family that functions as a negative regulator of MAPK signaling. MKP-1 is induced by oxidative stress, but the role of its induction in cell death is not fully understood. Here, we show that hydrogen peroxide (H2O2) induces MKP-1 and activates MAPKs. Induction of MKP-1 by H2O2 correlated with inactivation of p38 and c-Jun-NH2-kinase (JNK). Overexpression of MKP-1 increased cell resistance to H2O2-induced death. Furthermore, we show by small interfering RNA silencing that down-regulation of MKP-1 increases phosphorylated p38 and JNK and subsequent cell death induced by H2O2. More importantly, primary embryonic fibroblasts from mice lacking MKP-1 had a higher level of phosphorylated p38 and JNK and were more sensitive to H2O2-induced cell death compared with corresponding cells with MKP-1, indicating that p38 and JNK pathways may play important roles in H2O2-mediated cell death. Thus, these results suggest that activation of MKP-1 is a survival mechanism against oxidative damage. (Cancer Res 2006; 66(9): 4888-94)
Distinct Roles of Nonmuscle Myosin II Isoforms in the Regulation of MDA-MB-231 Breast Cancer Cell Spreading and Migration
Authors: Betapudi Venkaiah , Licate Lucila S. , Egelhoff Thomas T. 
Published: May 2006

Abstract
Initial stages of tumor cell metastasis involve an epithelial-mesenchyme transition that involves activation of amoeboid migration and loss of cell-cell adhesion. The actomyosin cytoskeleton has fundamental but poorly understood roles in these events. Myosin II, an abundant force-producing protein, has roles in cell body translocation and retraction of the posterior of the cell during migration. Recent studies have suggested that this protein may also have roles in leading edge protrusive events. The metastasis-promoting protein metastasin-1, a regulator of myosin II assembly, colocalizes with myosin IIA at the leading edge of cancer cells, suggesting direct roles for myosin II in metastatic behavior. We have assessed the roles of specific myosin II isoforms during lamellar spreading of MDA-MB-231 breast cancer cells on extracellular matrix. We find that the two major myosin II isoforms IIA and IIB are both expressed in these cells, and both are recruited dramatically to the lamellar margin during active spreading on fibronectin. There is also a transient increase in regulatory light chain phosphorylation that correlates the recruitment of myosin IIA and myosin IIB into this spreading margin. Pharmacologic inhibition of myosin II or myosin light chain kinase dramatically reduced spreading. Depletion of myosin IIA via small interfering RNA impaired migration but enhanced lamellar spreading, whereas depletion of myosin IIB impaired not only migration but also impaired initial rates of lamellar spreading. These results indicate that both isoforms are critical for the mechanics of cell migration, with myosin IIB seeming to have a preferential role in the mechanics of lamellar protrusion. (Cancer Res 2006; 66(9): 4725-33)