bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANLN Plays a Critical Role in Human Lung Carcinogenesis through the Activation of RHOA and by Involvement in the Phosphoinositide 3-Kinase/AKT Pathway
Authors: Suzuki Chie , Daigo Yataro , Ishikawa Nobuhisa , Kato Tatsuya , Hayama Satoshi , Ito Tomoo , Tsuchiya Eiju , Nakamura Yusuke 
Published: December 2005

Abstract
Gene expression profile analysis of non–small cell lung cancers (NSCLC) and subsequent functional analyses revealed that human ANLN, a homologue of anillin, an actin-binding protein in Drosophila, was transactivated in lung cancer cells and seemed to play a significant role in pulmonary carcinogenesis. Induction of small interfering RNAs against ANLN in NSCLC cells suppressed its expression and resulted in growth suppression; moreover, treatment with small interfering RNA yielded cells with larger morphology and multiple nuclei, which subsequently died. On the other hand, induction of exogenous expression of ANLN enhanced the migrating ability of mammalian cells by interacting with RHOA, a small guanosine triphosphatase, and inducing actin stress fibers. Interestingly, inhibition of phosphoinositide 3-kinase/AKT activity in NSCLC cells decreased the stability of ANLN and caused a reduction of the nuclear ANLN level. Immunohistochemical staining of nuclear ANLN on lung cancer tissue microarrays was associated with the poor survival of NSCLC patients, indicating that this molecule might serve as a prognostic indicator. Our data imply that up-regulation of ANLN is a common feature of the carcinogenetic process in lung tissue, and suggests that selective suppression of ANLN could be a promising approach for developing a new strategy to treat lung cancers. (Cancer Res 2005; 65(24): 11314-25)
Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments Anti-CD40 SGN-40–Induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications
Authors: Tai Yu-Tzu , Li Xian-Feng , Catley Laurence , Coffey Rory , Breitkreutz Iris , Bae Jooeun , Song Weihua , Podar Klaus , Hideshima Teru , Chauhan Dharminder , Schlossman Robert , Richardson Paul , Treon Steven P. , Grewal Iqbal S. , Munshi Nikhil C. , Anderson Kenneth C. 
Published: December 2005

AbstractSGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6–induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40–induced cytotoxicity against CD138+CD40+ MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40–induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G0 cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40–induced MM cell lysis, associated with an increased number of CD56+CD3− natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell–mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56+CD3− NK cells, facilitating IL-2–mediated activation of NK cells. In addition, lenalidomide induced the CD56dim NK subset, which are more potent mediators of ADCC against target MM cells than the CD56bright NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40–mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM. (Cancer Res 2005; 65(24): 11712-20)
Inhibition of DNA Methylation Sensitizes Glioblastoma for Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Destruction
Authors: Eramo Adriana , Pallini Roberto , Lotti Fiorenza , Sette Giovanni , Patti Mariella , Bartucci Monica , Ricci-Vitiani Lucia , Signore Michele , Stassi Giorgio , Larocca Luigi M. , Crinò Lucio , Peschle Cesare , De Maria Ruggero 
Published: December 2005

AbstractLife expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenous caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma resistance to therapeutic treatments. (Cancer Res 2005; 65(24): 11469-77)
Differentiation of Androgen-Independent Prostate Cancer PC-3 Cells Is Associated with Increased Nuclear Factor-κB Activity
Authors: Floryk Daniel , Huberman Eliezer 
Published: December 2005

Abstract
Recently, we have reported that inosine 5′-monophosphate dehydrogenase inhibitors, such as mycophenolic acid (MPA), induce the differentiation of PC-3 cells, which are derived from a human androgen-independent prostate cancer, into cells with a phenotype resembling maturing prostate secretory cells. Here, we describe such differentiation induced by the histone deacetylase inhibitor tributyrin. The maturation was defined by cytoplasmic vacuole production and induction of CD10, CD46, CD55, GRP78, keratin 17, and zinc-α-2-glycoprotein. To identify additional genes associated with tributyrin-induced PC-3 cell differentiation and to gain some insight into the mechanism that underlies this differentiation, we have, by means of microarray analyses, compared tributyrin-induced gene expression patterns with those of MPA, which initiates PC-3 cell differentiation by a dissimilar mode of action. We suggested that genes induced by both tributyrin and MPA would be most likely associated with differentiation rather than with the unique action of each particular inducer. Our results indicated that tributyrin or MPA induced the expression of a large number of common genes, including genes known or assumed to be NF-κB dependent. The NF-κB dependency of a group of these genes, which included the PC-3 cell differentiation marker keratin 17, was confirmed by using two common NF-κB activation inhibitors, Bay11-082 and TMB-8, and p65 subunit of NF-κB complex specific small interfering RNA. Taken together, our results implicate both NF-κB–dependent and NF-κB–independent genes in the processes leading to PC-3 cell differentiation induced by tributyrin and MPA. (Cancer Res 2005; 65(24): 11588-96)
BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to α-Folate Receptor–Overexpressing Tumors
Authors: Gibbs David D. , Theti Davinder S. , Wood Nadya , Green Matthew , Raynaud Florence , Valenti Melanie , Forster Martin D. , Mitchell Fraser , Bavetsias Vassilios , Henderson Elisa , Jackman Ann L. 
Published: December 2005

Abstract
BGC 945 is a cyclopenta[g]quinazoline–based, thymidylate synthase inhibitor specifically transported into α-folate receptor (α-FR)–overexpressing tumors. Affinity of BGC 945 for the α-FR is 70% of the high-affinity ligand folic acid. In contrast to conventional antifolates, BGC 945 has low affinity for the widely expressed reduced-folate carrier (RFC). The Ki for isolated thymidylate synthase is 1.2 nmol/L and the IC50 for inhibition of the growth of α-FR-negative mouse L1210 or human A431 cells is ∼7 μmol/L. In contrast, BGC 945 is highly potent in a range of α-FR-overexpressing human tumor cell lines (IC50 ∼1-300 nmol/L). Pharmacokinetic variables measured following i.v. injection of 100 mg/kg BGC 945 to KB tumor–bearing mice showed rapid plasma clearance (0.021 L/h) and tissue distribution. The terminal half-lives in plasma, liver, kidney, spleen, and tumor were 2, 0.6, 5, 21, and 28 hours, respectively. Tumor BGC 945 concentration at 24 hours was ∼1 nmol/g tissue, at least 10-fold higher than that in plasma or normal tissues. Inhibition of thymidylate synthase in tissues leads to increased incorporation of 5-[125I]-iodo-2′-deoxyuridine ([125I]dUrd) into DNA. Forty-eight hours after injection of 100 mg/kg 6RS-BGC 945 ([125I]dUrd injected at 24 hours), tumor was the only tissue with incorporation above control level (6-fold). The RFC-mediated thymidylate synthase inhibitor plevitrexed also increased uptake of [125I]dUrd in tumor (10-fold) but, in contrast, also caused increased incorporation in other normal tissues such as spleen and small bowel (4.5- and 4.6-fold, respectively). These data suggest that BGC 945 selectively inhibits thymidylate synthase in α-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. (Cancer Res 2005; 65(24): 11721-8)
Sequence Variants of Toll-Like Receptor 4 and Susceptibility to Prostate Cancer
Authors: Chen Yen-Ching , Giovannucci Edward , Lazarus Ross , Kraft Peter , Ketkar Shamika , Hunter David J. 
Published: December 2005

Abstract
Chronic inflammation has been hypothesized to be a risk factor for prostate cancer. The Toll-like receptor 4 (TLR4) presents the bacterial lipopolysaccharide (LPS), which interacts with ligand-binding protein and CD14 (LPS receptor) and activates expression of inflammatory genes through nuclear factor-κB and mitogen-activated protein kinase signaling. A previous case-control study found a modest association of a polymorphism in the TLR4 gene [11381G/C, GG versus GC/CC: odds ratio (OR), 1.26] with risk of prostate cancer. We assessed if sequence variants of TLR4 were associated with the risk of prostate cancer. In a nested case-control design within the Health Professionals Follow-up Study, we identified 700 participants with prostate cancer diagnosed after they had provided a blood specimen in 1993 and before January 2000. Controls were 700 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped 16 common (&gt;5%) single nucleotide polymorphisms (SNP) discovered in a resequencing study spanning TLR4 to test for association between sequence variation in TLR4 and prostate cancer. Homozygosity for the variant alleles of eight SNPs was associated with a statistically significantly lower risk of prostate cancer (TLR4_1893, TLR4_2032, TLR4_2437, TLR4_7764, TLR4_11912, TLR4_16649, TLR4_17050, and TLR4_17923), but the TLR4_15844 polymorphism corresponding to 11381G/C was not associated with prostate cancer (GG versus CG/CC: OR, 1.01; 95% confidence interval, 0.79-1.29). Six common haplotypes (cumulative frequency, 81%) were observed; the global test for association between haplotypes and prostate cancer was statistically significant (χ2 = 14.8 on 6 degrees of freedom; P = 0.02). Two common haplotypes were statistically significantly associated with altered risk of prostate cancer. Inherited polymorphisms of the innate immune gene TLR4 are associated with risk of prostate cancer. (Cancer Res 2005; 65(24): 11771-8)
Endothelin-1 Promotes Epithelial-to-Mesenchymal Transition in Human Ovarian Cancer Cells
Authors: Rosanò Laura , Spinella Francesca , Di Castro Valeriana , Nicotra Maria Rita , Dedhar Shoukat , de Herreros Antonio Garcia , Natali Pier Giorgio , Bagnato Anna 
Published: December 2005

Abstract
Despite considerable efforts to improve early detection and advances in chemotherapy, metastatic relapses remain a major challenge in the management of ovarian cancer. The endothelin A receptor (ETAR)/endothelin-1 (ET-1) axis has been shown to have a significant role in ovarian carcinoma by promoting tumorigenesis. Here we show that the ET-1/ETAR autocrine pathway drives epithelial-to-mesenchymal transition (EMT) in ovarian tumor cells by inducing a fibroblastoid and invasive phenotype, down-regulation of E-cadherin, increased levels of β-catenin, Snail, and other mesenchymal markers, and suppression of E-cadherin promoter activity. Activation of ETAR by ET-1 triggers an integrin-linked kinase (ILK)–mediated signaling pathway leading to glycogen synthase kinase-3β (GSK-3β) inhibition, Snail and β-catenin stabilization, and regulation of transcriptional programs that control EMT. Transfection of dominant negative ILK or exposure to an ILK inhibitor suppresses the ET-1-induced phosphorylation of GSK-3β as well as Snail and β-catenin protein stability, activity, and invasiveness, indicating that ET-1/ETAR–induced EMT-promoting effects depend on ILK. ETAR blockade by specific antagonists or reduction by ETAR RNA interference reverses EMT and cell invasion by inhibiting autocrine signaling pathways. In ovarian carcinoma xenografts, ABT-627, a specific ETAR antagonist, suppresses EMT determinants and tumor growth. In human ovarian cancers, ETAR expression is associated with E-cadherin down-regulation, N-cadherin expression, and tumor grade. Collectively, these findings provide evidence of a critical role for the ET-1/ETAR axis during distinct steps of ovarian carcinoma progression and identify novel targets of therapeutic intervention. (Cancer Res 2005; 65(24): 11649-57)
Mutually Exclusive Cyclin-Dependent Kinase 4/Cyclin D1 and Cyclin-Dependent Kinase 6/Cyclin D2 Pairing Inactivates Retinoblastoma Protein and Promotes Cell Cycle Dysregulation in Multiple Myeloma
Authors: Ely Scott , Di Liberto Maurizio , Niesvizky Ruben , Baughn Linda B. , Cho Hearn J. , Hatada Eunice N. , Knowles Daniel M. , Lane Joseph , Chen-Kiang Selina 
Published: December 2005

AbstractMultiple myeloma, the second most common hematopoietic cancer, ultimately becomes refractory to treatment when self-renewing multiple myeloma cells begin unrestrained proliferation by unknown mechanisms. Here, we show that one, but not more than one, of the three early G1 D cyclins is elevated in each case of multiple myeloma. Cyclin D1 or D3 expression does not vary in the clinical course, but that alone is insufficient to promote cell cycle progression unless cyclin-dependent kinase 4 (cdk4) is also elevated, in the absence of cdk6, to phosphorylate the retinoblastoma protein (Rb). By contrast, cyclin D2 and cdk6 are coordinately increased, thereby overriding the inhibition by cdk inhibitors p18INK4c and p27Kip1 and phosphorylating Rb in conjunction with the existing cdk4. Thus, cyclin D1 pairs exclusively with cdk4 and cdk6 pairs only with cyclin D2, although cyclin D2 can also pair with cdk4 in multiple myeloma cells. The basis for this novel and specific cdk/D cyclin pairing lies in differential transcriptional activation. In addition, cyclin D1– or cyclin D3–expressing multiple myeloma cells are uniformly distributed in the bone marrow, whereas cdk6-specific phosphorylation of Rb occurs in discrete foci of bone marrow multiple myeloma cells before proliferation early in the clinical course and is then heightened with proliferation and disease progression. Mutually exclusive cdk4/cyclin D1 and cdk6/cyclin D2 pairing, therefore, is likely to be a critical determinant for cell cycle reentry and progression and may play a pivotal role in the expansion of self-renewing multiple myeloma cells. (Cancer Res 2005; 65(24): 11345-53)
The Critical Role of 15-Lipoxygenase-1 in Colorectal Epithelial Cell Terminal Differentiation and Tumorigenesis
Authors: Shureiqi Imad , Wu Yuanqing , Chen Dongning , Yang Xiu L. , Guan Baoxiang , Morris Jeffrey S. , Yang Peiying , Newman Robert A. , Broaddus Russell , Hamilton Stanley R. , Lynch Patrick , Levin Bernard , Fischer Susan M. , Lippman Scott M. 
Published: December 2005

Abstract
Terminal differentiation is an important event for maintaining normal homeostasis in the colorectal epithelium, and the loss of apoptosis is an important mechanism underlying colorectal tumorigenesis. The very limited current data on the role of lipoxygenase (LOX) metabolism in tumorigenesis suggests that the oxidative metabolism of linoleic and arachidonic acid possibly shifts from producing antitumorigenic 15-LOX-1 and 15-LOX-2 products to producing protumorigenic 5-LOX and 12-LOX products. We examined whether this shift occurs in vitro in the human colon cancer cell line Caco-2 in association with the loss of terminal differentiation and apoptosis, or in vivo during the formation of colorectal adenomas in patients with familial adenomatous polyposis (FAP). Restoring terminal differentiation and apoptosis of Caco-2 cells increased the mRNA levels of 5-LOX, 15-LOX-2, and 15-LOX-1, but the only significant increases in protein expression and enzymatic activity were of 15-LOX-1. In FAP patients, 15-LOX-1 expression and activity were significantly down-regulated in adenomas (compared with paired nonneoplastic epithelial mucosa), whereas 5-LOX and 15-LOX-2 protein expressions and enzymatic activities were not. We conducted a validation study with immunohistochemical testing in a second group of FAP patients; 15-LOX-1 expression was down-regulated in colorectal adenomas (compared with nonneoplastic epithelial mucosa) in 87% (13 of 15) of this group. We confirmed the mechanistic relevance of these findings by demonstrating that ectopically restoring 15-LOX-1 expression reestablished apoptosis in Caco-2 cells. Therefore, 15-LOX-1 down-regulation rather than a shift in the balance of LOXs is likely the dominant alteration in LOX metabolism which contributes to colorectal tumorigenesis by repressing apoptosis. (Cancer Res 2005; 65(24): 11486-92)
Expression of Endogenous OncogenicV600EB-rafInduces Proliferation and Developmental Defects in Mice and Transformation of Primary Fibroblasts
Authors: Mercer Kathryn , Giblett Susan , Green Stuart , Lloyd David , DaRocha Dias Silvy , Plumb Mark , Marais Richard , Pritchard Catrin 
Published: December 2005

AbstractMutations of the human B-RAF gene are detected in ∼8% of cancer samples, primarily in cutaneous melanomas (70%). The most common mutation (90%) is a valine-to-glutamic acid mutation at residue 600 (V600E; formerly V599E according to previous nomenclature). Using a Cre/Lox approach, we have generated a conditional knock-in allele of V600EB-raf in mice. We show that widespread expression of V600EB-Raf cannot be tolerated in embryonic development, with embryos dying ∼7.5 dpc. Directed expression of mutant V600EB-Raf to somatic tissues using the IFN-inducible Mx1-Cre mouse strain induces a proliferative disorder and bone marrow failure with evidence of nonlymphoid neoplasia of the histiocytic type leading to death within 4 weeks of age. However, expression of mutant B-Raf does not alter the proliferation profile of all somatic tissues. In primary mouse embryonic fibroblasts, expression of endogenous V600EB-Raf induces morphologic transformation, increased cell proliferation, and loss of contact inhibition. Thus, V600EB-Raf is able to induce several hallmarks of transformation in some primary mouse cells without evidence for the involvement of a cooperating oncogene or tumor suppressor gene. (Cancer Res 2005; 65(24): 11493-500)
Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins
Authors: Zacharek Sima J. , Xiong Yue , Shumway Stuart D. 
Published: December 2005

Abstract
The metazoan cell cycle is driven by the timely and composite activities of cyclin-dependent kinases (CDKs). Among these, cyclin D- and cyclin E-dependent kinases phosphorylate the pRb family proteins during G1 phase of the cell cycle and thereby advance cells beyond the restriction point. Increasing evidence suggests that cyclin D-dependent kinases might affect events other than Rb pathway-mediated entry into S phase, such as accumulation of cell mass. However, little is known about cyclin D activity toward Rb-independent pathway(s) or non-pRb substrates. In this article, we show that the tumor suppressor TSC2 is a cyclin D binding protein. Coexpression of cyclin D1-CDK4/6 in cultured cells leads to increased phosphorylation and decreased detection of both TSC2 and TSC1, and promotes the phosphorylation of the mTOR substrates, 4E-BP1 and S6K1, two key effectors of cell growth that are negatively regulated by the TSC1-TSC2 complex. At the cellular level, ectopic expression of cyclin D1 restores the cell size decrease caused by TSC1-TSC2 expression. Intriguingly, down-regulation of TSC proteins was also observed by the expression of a mutant cyclin D1 that is unable to bind to CDK4/6, or by the coexpression of cyclin D1 with either an INK4 inhibitor or with catalytically inactive CDK6, indicating that cyclin D may regulate TSC1-TSC2 independently of CDK4/6. Together, these observations suggest that mammalian D-type cyclins participate in cell growth control through negative regulation of TSC1-TSC2 function. (Cancer Res 2005; 65(24): 11354-60)
Headpin: A Serpin with Endogenous and Exogenous Suppression of Angiogenesis
Authors: Shellenberger Thomas D. , Mazumdar Abhijit , Henderson Ying , Briggs Katrina , Wang Mary , Chattopadhyay Chandrani , Jayakumar Arumugam , Frederick Mitchell , Clayman Gary L. 
Published: December 2005

Abstract
Headpin is a novel serine proteinase inhibitor (serpin) with constitutive mRNA expression in histologically normal oral mucosa but with lost or down-regulated expression in head and neck squamous cell carcinoma. Several serpin family members are similarly lost in multiple cancer types and hold tumor suppressor functions including the inhibition of angiogenesis. However, the functional significance for the loss of headpin expression in cancer is not known. Using immunohistochemical analysis of invasive squamous cell carcinoma and matched normal squamous mucosa of patient specimens, headpin expression was lost or down-regulated in the vast majority of tumor specimens. We investigated the functions of exogenous recombinant headpin and endogenously expressed headpin related to angiogenesis. In a rat corneal assay of neovascularization, recombinant headpin protein blocked in vivo angiogenesis mediated by interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF). In assays of cellular events in angiogenesis, headpin blocked the invasion, migration, and tube formation of endothelial cells. In light of our findings of nuclear subcellular localization of headpin, we investigated the expression and secretion of angiogenic factors and found reduced mRNA, protein, and promoter activities of IL-8 and VEGF. Finally, using a murine flank tumor model, headpin expression reduced growth and microvessel density in tumors derived from headpin-expressing UMSCC1 cells relative to those from vector control cells. These findings of nuclear regulatory functions of a serpin in the inhibition of angiogenesis bring new understanding to the cellular and molecular mechanisms of serpins. Therefore, this novel serpin targets diverse mechanisms against tumor angiogenesis on which to base therapeutic strategies. (Cancer Res 2005; 65(24): 11501-9)