bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of p53 Enhances Selenite-Induced Superoxide Production and Apoptosis in Human Prostate Cancer Cells
Authors: Zhao Rui , Xiang Nong , Domann Frederick E. , Zhong Weixiong 
Published: February 2006

AbstractAlthough the anticancer effects of selenium have been shown in clinical, preclinical, and laboratory studies, the underlying mechanism(s) remains unclear. Our previous study showed that sodium selenite induced LNCaP human prostate cancer cell apoptosis in association with production of reactive oxygen species, alteration of cell redox state, and mitochondrial damage. In the present study, we showed that selenite-induced apoptosis was superoxide mediated and p53 dependent via mitochondrial pathways. In addition, we also showed that superoxide production by selenite was p53 dependent. Our study showed that wild-type p53–expressing LNCaP cells were more sensitive to selenite-induced apoptosis than p53-null PC3 cells. Selenite treatment resulted in high levels of superoxide production in LNCaP cells but only low levels in PC3 cells. LNCaP cells also showed sequential increases in levels of phosphorylated p53 (serine 15), total p53, Bax, and p21Waf1 proteins following selenite treatment. The effects of selenite were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. LNCaP cells treated with selenite also showed p53 translocation to mitochondria, cytochrome c release into the cytosol, and activation of caspase-9. On the other hand, restoration of wild-type p53 expression in PC3 cells increased cellular sensitivity to selenite and resulted in increased superoxide production, caspase-9 activation, and apoptosis following selenite treatment. These results suggest that selenite induces apoptosis by producing superoxide to activate p53 and to induce p53 mitochondrial translocation. Activation of p53 in turn synergistically enhances superoxide production and apoptosis induced by selenite. (Cancer Res 2006; 66(4): 2296-304)
Multiple Oncogenic Changes (K-RASV12, p53 Knockdown,Mutant EGFRs, p16Bypass, Telomerase) Are Not Sufficient to Confer a Full Malignant Phenotype on Human Bronchial Epithelial Cells
Authors: Sato Mitsuo , Vaughan Melville B. , Girard Luc , Peyton Michael , Lee Woochang , Shames David S. , Ramirez Ruben D. , Sunaga Noriaki , Gazdar Adi F. , Shay Jerry W. , Minna John D. 
Published: February 2006

AbstractWe evaluated the contribution of three genetic alterations (p53 knockdown, K-RASV12, and mutant EGFR) to lung tumorigenesis using human bronchial epithelial cells (HBEC) immortalized with telomerase and Cdk4-mediated p16 bypass. RNA interference p53 knockdown or oncogenic K-RASV12 resulted in enhanced anchorage-independent growth and increased saturation density of HBECs. The combination of p53 knockdown and K-RASV12 further enhanced the tumorigenic phenotype with increased growth in soft agar and an invasive phenotype in three-dimensional organotypic cultures but failed to cause HBECs to form tumors in nude mice. Growth of HBECs was highly dependent on epidermal growth factor (EGF) and completely inhibited by EGF receptor (EGFR) tyrosine kinase inhibitors, which induced G1 arrest. Introduction of EGFR mutations E746-A750 del and L858R progressed HBECs toward malignancy as measured by soft agar growth, including EGF-independent growth, but failed to induce tumor formation. Mutant EGFRs were associated with higher levels of phospho-Akt, phospho–signal transducers and activators of transcription 3 [but not phospho-extracellular signal-regulated kinase (ERK) 1/2], and increased expression of DUSP6/MKP-3 phosphatase (an inhibitor of phospho-ERK1/2). These results indicate that (a) the HBEC model system is a powerful new approach to assess the contribution of individual and combinations of genetic alterations to lung cancer pathogenesis; (b) a combination of four genetic alterations, including human telomerase reverse transcriptase overexpression, bypass of p16/RB and p53 pathways, and mutant K-RASV12 or mutant EGFR, is still not sufficient for HBECs to completely transform to cancer; and (c) EGFR tyrosine kinase inhibitors inhibit the growth of preneoplastic HBEC cells, suggesting their potential for chemoprevention. (Cancer Res 2006; 66(4): 2116-28)
Protein Kinase B/Akt-Dependent Phosphorylation of Glycogen Synthase Kinase-3β in Irradiated Vascular Endothelium
Authors: Tan Jiahua , Geng Ling , Yazlovitskaya Eugenia M. , Hallahan Dennis E. 
Published: February 2006

Abstract
The vascular endothelium plays a critical role in the response of cancer to ionizing radiation. Activation of the phosphoinositide-3-kinase/Akt pathway is one initial signaling event in irradiated endothelial cells. Specifically, a low dose of ionizing radiation (3 Gy) induces phosphorylation of Akt at Ser473 in the vascular endothelium within minutes of irradiation. However, signaling events that are downstream of Akt have not been well defined. Here, we show that phosphorylation of the Akt downstream target glycogen synthase kinase-3β (GSK-3β) at Ser9 also occurred within minutes of exposure to ionizing radiation. In addition, ionizing radiation caused the dissociation of GSK-3β from the cell membrane, consistent with the inactivation of GSK-3β enzyme activity. Overexpression of the dominant negative mutant Akt attenuated GSK-3β phosphorylation at Ser9 and enhanced radiation-induced apoptosis. X-irradiated endothelial cells formed capillaries in both in vitro and in vivo models, whereas overexpression of the dominant negative mutant Akt inhibited capillary tubule formation. Studies using GSK-3β antagonists showed that GSK-3β activity was required for apoptosis in endothelial cells treated simultaneously with Akt antagonists and radiation. In mouse vascular models, radiation-induced microvascular destruction in response to Akt antagonists also required GSK-3β function. These data indicate that on exposure of vascular endothelium to ionizing radiation, activation of Akt signaling contributes to GSK-3β inhibition, which in turn promotes endothelial cell survival and capillary formation. Thus, pharmacologic regulation of Akt/GSK-3β signaling may present a new approach to the radiation response in the tumor microvasculature. (Cancer Res 2006; 66(4): 2320-7)
Integrin α4β1 Promotes Monocyte Trafficking and Angiogenesis in Tumors
Authors: Jin Hui , Su Jingmei , Garmy-Susini Barbara , Kleeman Jeanine , Varner Judy 
Published: February 2006

Abstract
Monocytes and macrophages extensively colonize solid tumors, where they are thought to promote tumor angiogenesis. Here, we show that integrin α4β1 (VLA4) promotes the invasion of tumors by myeloid cells and subsequent neovascularization. Antagonists of integrin α4β1, but not of other integrins, blocked the adhesion of monocytes to endothelium in vitro and in vivo as well as their extravasation into tumor tissue. These antagonists prevented monocyte stimulation of angiogenesis in vivo, macrophage colonization of tumors, and tumor angiogenesis. These studies indicate the usefulness of antagonists of integrin α4β1 in suppressing macrophage colonization of tumors and subsequent tumor angiogenesis. These studies further indicate that suppression of myeloid cell homing to tumors could be a useful supplementary approach to suppress tumor angiogenesis and growth. (Cancer Res 2006; 66(4):2146-52)
Identification of the IFITM Family as a New Molecular Marker in Human Colorectal Tumors
Authors: Andreu Pauline , Colnot Sabine , Godard Cécile , Laurent-Puig Pierre , Lamarque Dominique , Kahn Axel , Perret Christine , Romagnolo Béatrice 
Published: February 2006

Abstract
We analyzed the expression profiles of intestinal adenomas from a new murine familial adenomatous polyposis model (ApcΔ14/+) using suppression subtractive hybridization to identify novel diagnostic markers of colorectal carcinogenesis. We identified 18 candidate genes having increased expression levels in the adenoma. Subsequent Northern blotting, real-time reverse transcription-PCR, and in situ hybridization analysis confirmed their induction in β-catenin-activated epithelial cells of murine adenomas. We showed that most of the genes also have altered expression levels in human colonic adenomas and carcinomas. We focused on the IFITM genes that encode IFN-inducible transmembrane proteins. Serial analyses of gene expression levels revealed high levels of expression in early and late intestinal neoplasm in both mice and humans. Using a conditional mouse model of Apc inactivation and a human colon carcinoma cell line, we showed that IFITM gene expression is rapidly induced after activation of the β-catenin signaling. Using a large-scale analysis of human tumors, we showed that IFITM gene expression is significantly up-regulated specifically in colorectal tumors and thus may be a useful diagnostic tool in these tumors. (Cancer Res 2006; 66(4): 1949-55)
Role of Protein Kinase CK2 in the Regulation of Tumor Necrosis Factor–Related Apoptosis Inducing Ligand–Induced Apoptosis in Prostate Cancer Cells
Authors: Wang Guixia , Ahmad Kashif A. , Ahmed Khalil 
Published: February 2006

Abstract
Protein kinase CK2 (formerly casein kinase 2 or II) is a ubiquitous and highly conserved protein Ser/Thr kinase that plays diverse roles such as in cell proliferation and apoptosis. With respect to the latter, we originally showed that elevated CK2 could suppress various types of apoptosis in prostate cancer cells; however, the downstream pathways that respond to CK2 for mediating the suppression of apoptosis have not been fully elucidated. Here, we report studies on the role of CK2 in influencing activities associated with tumor necrosis factor–related ligand (TRAIL/Apo2-L)–mediated apoptosis in prostate carcinoma cells. To that end, we show that both androgen-insensitive (PC-3) and androgen-sensitive (ALVA-41) prostate cancer cells are sensitized to TRAIL by chemical inhibition of CK2 using its specific inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB). Furthermore, we have shown that overexpression of CK2α using pcDNA6-CK2α protected prostatic cancer cells from TRAIL-mediated apoptosis by affecting various activities associated with this process. Thus, overexpression of CK2 resulted in the suppression of TRAIL-induced apoptosis via its effects on the activation of caspases, DNA fragmentation, and downstream cleavage of lamin A. In addition, the overexpression of CK2 blocked the mitochondrial apoptosis machinery engaged by TRAIL. These findings define the important role of CK2 in TRAIL signaling in androgen-sensitive and -insensitive prostatic carcinoma cells. Our data support the potential usefulness of anticancer strategies that may involve the combination of TRAIL and down-regulation of CK2. (Cancer Res 2006; 66(4): 2242-9)
Parathyroid Hormone–Related Protein Localization in Breast Cancers Predict Improved Prognosis
Authors: Henderson Michael A. , Danks Janine A. , Slavin John L. , Byrnes Graham B. , Choong Peter F.M. , Spillane John B. , Hopper John L. , Martin T. John 
Published: February 2006

Abstract
In a prospective study of 526 consecutive patients with operable breast cancer, the significance of positive parathyroid hormone–related protein (PTHrP) staining by immunohistology has been evaluated for a median of 10-year follow-up. Improved survival was observed for the 79% of tumors which stained positively for PTHrP [estimated univariate hazard ratio, 0.43; 95% confidence interval (95% CI), 0.30-0.62; P &lt; 0.001]. Adjustments for N stage, progesterone receptor status, and log tumor size changed this estimate only slightly to 0.47 (95% CI, 0.63-0.69; P = 0.001). Patients with PTHrP-positive primary tumors were less likely to develop bone metastases (hazard ratio, 0.63; 95% CI, 0.41-0.98; P = 0.04). PTHrP status was associated with estrogen receptor (P = 0.01), progesterone receptor (P = 0.03), and menopausal status (P = 0.006) but was not significantly associated with tumor size, vascular invasion, tumor grade, or patient age. Of 19 patients requiring surgery for bone metastases, the primary cancers were PTHrP negative in seven, all but one of whom had PTHrP-positive bone metastases. All 12 patients with PTHrP-positive primary cancers also had positive bone metastases. We conclude that increased production of PTHrP by breast cancers confers on them a less invasive phenotype, an effect distinct from the bone resorption–stimulating action that favors bone metastasis. It is likely that the latter property is influenced by factors in the bone microenvironment. (Cancer Res 2006; 66(4): 2250-6)
Cancer Risk Assessment at the Atomic Level
Authors: Monteiro Alvaro N.A. , Couch Fergus J. 
Published: February 2006

Abstract
A flurry of articles on the structure of different domains of BRCA1 and BRCA2 have not only shed light on the biology of these proteins but have also raised hopes that these data could eventually be used to infer cancer association for a large number of inherited missense mutations whose effect on protein function is unclear. (Cancer Res 2006; 66(4): 1897-9)
3-Methylcholanthrene and Other Aryl Hydrocarbon Receptor Agonists Directly Activate Estrogen Receptor α
Authors: Abdelrahim Maen , Ariazi Eric , Kim Kyounghyun , Khan Shaheen , Barhoumi Rola , Burghardt Robert , Liu Shengxi , Hill Denise , Finnell Richard , Wlodarczyk Bogdan , Jordan V. Craig , Safe Stephen 
Published: February 2006

Abstract
3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor α (ERα) interactions. In this study, we used 3MC and 3,3′,4,4′,5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ERα but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ERα, and this was confirmed in a competitive ERα binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ERα/YFP-ERα interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ERα (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ERα-dependent transactivation and extend the number of ligands that activate both AhR and ERα. (Cancer Res 2006; 66(4): 2459-67)
Cancer Stem Cells: An Old Idea—A Paradigm Shift
Authors: Wicha Max S. , Liu Suling , Dontu Gabriela 
Published: February 2006

Abstract
Although the concept that cancers arise from “stem cells” or “germ cells” was first proposed about 150 years ago, it is only recently that advances in stem cell biology have given new impetus to the “cancer stem cell hypothesis.” Two important related concepts of this hypothesis are that (a) tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of self-renewal. As a result of this, (b) tumors contain a cellular subcomponent that retains key stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation albeit aberrant that contributes to cellular heterogeneity. Recent experimental evidence in a variety of tumors has lent strong support to the cancer stem cell hypothesis that represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology. This hypothesis has fundamental implications for cancer risk assessment, early detection, prognostication, and prevention. Furthermore, the current development of cancer therapeutics based on tumor regression may have produced agents that kill differentiated tumor cells while sparing the rare cancer stem cell population. The development of more effective cancer therapies may thus require targeting this important cell population. (Cancer Res 2006; 66(4): 1883-90)
p53 Regulates Cellular Resistance to Complement Lysis through Enhanced Expression of CD59
Authors: Donev Rossen M. , Cole Duncan S. , Sivasankar Baalasubramanian , Hughes Timothy R. , Morgan B. Paul 
Published: February 2006

AbstractIt has been recently hypothesized that the CD59 gene has two putative p53-responsive elements that may be involved in defense of host cells from damage by the complement system in inflammation. Here we have examined the roles of these putative p53-binding sequences within the CD59 gene in regulation of CD59 expression. We have shown that both of these potential responsive elements bind p53 in vitro. Knocking down expression of p53 using small interfering RNA led to a 6-fold decrease in CD59 protein expression in HeLa cells. We have previously observed a decrease of CD59 in camptothecin-induced apoptotic IMR32 cells, whereas expression was increased in the surviving fraction compared with untreated cells. Here, we have shown that these changes are associated with altered expression levels and acetylation status of p53. We have also shown that acetylation status of p53 regulates CD59 expression on cells exposed to inflammatory cytokines to model inflammation. Our data suggest that p53 and in vivo positive/negative regulators of p53 could be used to modulate susceptibility of tumor cells to complement lysis in chemotherapy. (Cancer Res 2006; 66(4): 2451-8)
Role of the CXCL12/CXCR4 Axis in Peritoneal Carcinomatosis of Gastric Cancer
Authors: Yasumoto Kazuo , Koizumi Keiichi , Kawashima Atsuhiro , Saitoh Yurika , Arita Yoshihisa , Shinohara Kanna , Minami Takayuki , Nakayama Takashi , Sakurai Hiroaki , Takahashi Yutaka , Yoshie Osamu , Saiki Ikuo 
Published: February 2006

Abstract
Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P &lt; 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma. (Cancer Res 2006; 66(4): 2181-7)
Identifying Cancer Stem Cells in Solid Tumors: Case Not Proven
Authors: Hill Richard P. 
Published: February 2006

AbstractBuilding on studies of leukemia, a number of recent articles have reported data suggesting that cancer stem cells could be isolated from solid human cancers. Some of these reports have speculated that the isolation of these cells will allow the identification of the specific molecular properties that can be targeted for therapeutic purposes. Although previous work with animal model systems also suggests the presence of stem cells in solid tumors, there remain many uncertainties, both theoretical and technical, about the interpretation of the current results. The case that a small proportion of cells in solid tumors are specific cancer stem cells and that these cells can be successfully identified and isolated has not yet been proven. (Cancer Res 2006; 66(4): 1891-6)
Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model
Authors: Boerboom Derek , White Lisa D. , Dalle Sophie , Courty José , Richards JoAnne S. 
Published: February 2006

Abstract
Wnt/β-catenin signaling is normally involved in embryonic development and tissue homeostasis, and its misregulation leads to several forms of cancer. We have reported that misregulated Wnt/β-catenin signaling occurs in ovarian granulosa cell tumors (GCT) and have created the Catnbflox(ex3)/+;Amhr2cre/+ mouse model, which expresses a dominant-stable mutant of β-catenin in granulosa cells and develops late-onset GCT. To study the mechanisms leading to GCT development, gene expression analysis was done using microarrays comparing Catnbflox(ex3)/+;Amhr2cre/+ ovaries bearing pretumoral lesions with control ovaries. Overexpressed genes identified in Catnbflox(ex3)/+;Amhr2cre/+ ovaries included the Wnt/β-catenin signaling antagonists Wif1, Nkd1, Dkk4, and Axin2, consistent with the induction of negative feedback loops that counteract uncontrolled Wnt/β-catenin signaling. Expression of the antagonists was localized to cells forming the pretumoral lesions but not to normal granulosa cells. Microarray analyses also revealed the ectopic expression of bone markers, including Ibsp, Cdkn1c, Bmp4, and Tnfrsf11b, as well as neuronal/neurosecretory cell markers, such as Cck, Amph, Pitx1, and Sp5. Increased expression of the gene encoding the cytokine pleiotrophin was also found in Catnbflox(ex3)/+;Amhr2cre/+ ovaries and GCT but was not associated with increased serum pleiotrophin levels. In situ hybridization analyses using GCT from Catnbflox(ex3)/+;Amhr2cre/+ mice revealed that Wnt/β-catenin antagonists and neuronal markers localized to a particular cell population, whereas the bone markers localized to a distinct cell type associated with areas of osseous metaplasia. Together, these results suggest that misregulated Wnt/β-catenin signaling alters the fate of granulosa cells and that the GCT that arise in Catnbflox(ex3)/+;Amhr2cre/+ mice result from the clonal expansion of metaplastic cells. (Cancer Res 2006; 66(4): 1964-73)