bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death
Authors: Steták Attila , Veress Réka , Ovádi Judit , Csermely Péter , Kéri György , Ullrich Axel 
Published: February 2007

Abstract
Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during oncogenesis. Here, we show that both somatostatin and the structural analogue TT-232 interact with the PKM subtype. We further show that the PKM2 is translocated to the nucleus in response to TT-232 and different apoptotic agents. Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. These results show that the tumor marker PKM2 plays a general role in caspase-independent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development. [Cancer Res 2007;67(4):1602–8]
G Protein–Coupled Receptor 30 (GPR30) Mediates Gene Expression Changes and Growth Response to 17β-Estradiol and Selective GPR30 Ligand G-1 in Ovarian Cancer Cells
Authors: Albanito Lidia , Madeo Antonio , Lappano Rosamaria , Vivacqua Adele , Rago Vittoria , Carpino Amalia , Oprea Tudor I. , Prossnitz Eric R. , Musti Anna Maria , Andò Sebastiano , Maggiolini Marcello 
Published: February 2007

AbstractEstrogens play a crucial role in the development of ovarian tumors; however, the signal transduction pathways involved in hormone action are still poorly defined. The orphan G protein–coupled receptor 30 (GPR30) mediates the nongenomic signaling of 17β-estradiol (E2) in a variety of estrogen-sensitive cancer cells through activation of the epidermal growth factor receptor (EGFR) pathway. Whether estrogen receptor α (ERα) also contributes to GPR30/EGFR signaling is less understood. Here, we show that, in ERα-positive BG-1 ovarian cancer cells, both E2 and the GPR30-selective ligand G-1 induced c-fos expression and estrogen-responsive element (ERE)-independent activity of a c-fos reporter gene, whereas only E2 stimulated an ERE-responsive reporter gene, indicating that GPR30 signaling does not activate ERα-mediated transcription. Similarly, both ligands up-regulated cyclin D1, cyclin E, and cyclin A, whereas only E2 enhanced progesterone receptor expression. Moreover, both GPR30 and ERα expression are required for c-fos stimulation and extracellular signal-regulated kinase (ERK) activation in response to either E2 or G-1. Inhibition of the EGFR transduction pathway inhibited c-fos stimulation and ERK activation by either ligand, suggesting that in ovarian cancer cells GPR30/EGFR signaling relays on ERα expression. Interestingly, we show that both GPR30 and ERα expression along with active EGFR signaling are required for E2-stimulated and G-1–stimulated proliferation of ovarian cancer cells. Because G-1 was able to induce both c-fos expression and proliferation in the ERα-negative/GPR30-positive SKBR3 breast cancer cells, the requirement for ERα expression in GPR30/EGFR signaling may depend on the specific cellular context of different tumor types. [Cancer Res 2007;67(4):1859–66]
Human Mucin 1 Oncoprotein Represses Transcription of the p53 Tumor Suppressor Gene
Authors: Wei Xiaolong , Xu Hai , Kufe Donald 
Published: February 2007

Abstract
The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in human breast cancers and induces transformation. The MUC1 COOH-terminal subunit (MUC1-C) is targeted to the nucleus of transformed cells, where it interacts with p53 and regulates p53-mediated transcription. The present studies show that MUC1 represses activation of the p53 gene and that MUC1-C occupies the PE21 element in the p53 proximal promoter. Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21. The results also show that MUC1-C increases the recruitment of histone deacetylases 1/3, deacetylation of core histones, and repression of p53 transcription. These findings indicate that overexpression of MUC1, as found in human breast cancer cells, is of functional importance to repression of the p53 gene. [Cancer Res 2007;67(4):1853–8]
Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways
Authors: Niu Guilian , Carter W. Bradford 
Published: February 2007

Abstract
Abnormal activation of human epidermal growth factor receptor 2 (HER2; ErbB-2) in breast tumors results in increased metastasis and angiogenesis, as well as reduced survival. Here, we show that angiopoietin-2 (Ang-2) expression correlates with HER2 activity in human breast cancer cell lines. Inhibiting HER2 activity with anti-HER2 monoclonal antibody trastuzumab (Herceptin) or HER2 short interfering RNA in tumor cells down-regulates Ang-2 expression. Consistent with the important roles of AKT and mitogen-activated protein kinase in the HER2 signaling pathway, AKT and ERK mitogen-activated protein kinase (MAPK) kinase activity is necessary for Ang-2 up-regulation by HER2. Moreover, overexpression of HER2 protein up-regulates Ang-2 expression. Heregulin-β1–induced Ang-2 up-regulation is abrogated when AKT and ERK kinase activity are blocked. Immunohistochemical analysis of HER2 and Ang-2 proteins in human breast carcinomas shows that Ang-2 expression in breast cancer correlates with HER2 expression. These studies provide evidence that the Ang-2 gene is regulated by HER2 activity in breast cancer, and propose an additional mechanism for HER2 contributing to tumor angiogenesis and metastasis. [Cancer Res 2007;67(4):1487–93]
Gonadotropin-Releasing Hormone Type II Antagonists Induce Apoptotic Cell Death in Human Endometrial and Ovarian Cancer Cells In vitro and In vivo
Authors: Fister Stefanie , Günthert Andreas R. , Emons Günter , Gründker Carsten 
Published: February 2007

Abstract
In human endometrial and ovarian cancers, gonadotropin-releasing hormone type I (GnRH-I), GnRH-II, and their receptors are parts of a negative autocrine regulatory system of cell proliferation. Based on a tumor-specific signal transduction, GnRH-I and GnRH-II agonists inhibit the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in down-regulation of cancer cell proliferation. Induction of apoptosis is not involved. In this study, we show that treatment of human endometrial and ovarian cancer cells with GnRH-II antagonists results in apoptotic cell death via dose-dependent activation of caspase-3. The antitumor effects of the GnRH-II antagonists could be confirmed in nude mice. GnRH-II antagonists inhibited the growth of xenotransplants of human endometrial and ovarian cancers in nude mice significantly, without any apparent side effects. Thus, GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for endometrial and ovarian cancers. [Cancer Res 2007;67(4):1750–6]
The Human Papillomavirus E6 Oncogene Dysregulates the Cell Cycle and Contributes to Cervical Carcinogenesis through Two Independent Activities
Authors: Shai Anny , Brake Tiffany , Somoza Chamorro , Lambert Paul F. 
Published: February 2007

Abstract
Cervical cancer is a leading cause of death due to cancer among women worldwide. Using transgenic mice to dissect the contributions of the human papillomavirus (HPV) 16 E6 and E7 oncogenes in cervical cancer, E7 was identified previously to be the dominant oncogene. Specifically, when treated with exogenous estrogen for 6 months, E7 transgenic mice developed cancer throughout the reproductive tract, but E6 transgenic mice did not. E6 contributed to carcinogenesis of the reproductive tract, as E6/E7 double transgenic mice treated for 6 months with estrogen developed larger cancers than E7 transgenic mice. In the current study, we investigated whether the E6 oncogene alone could cooperate with estrogen to induce cervical cancer after an extended estrogen treatment period of 9 months. We found that the E6 oncogene synergizes with estrogen to induce cervical cancer after 9 months, indicating that E6 has a weaker but detectable oncogenic potential in the reproductive tract compared with the E7 oncogene. Using transgenic mice that express mutant forms of HPV16 E6, we determined that the interactions of E6 with cellular α-helix and PDZ partners correlate with its ability to induce cervical carcinogenesis. In analyzing the tumors arising in E6 transgenic mice, we learned that E6 induces expression of the E2F-responsive genes, Mcm7 and cyclin E, in the absence of the E7 oncogene. E6 also prevented the expression of p16 in tumors of the reproductive tract through a mechanism mediated by the interaction of E6 with α-helix partners. [Cancer Res 2007;67(4):1626–35]
Younger Age of Cancer Initiation Is Associated with Shorter Telomere Length in Li-Fraumeni Syndrome
Authors: Tabori Uri , Nanda Sonia , Druker Harriet , Lees Jodi , Malkin David 
Published: February 2007

Abstract
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P &lt; 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical TP53/MDM2-SNP309 genotypes. Furthermore, telomere shortening could predict genetic anticipation observed in LFS and may serve as the first rational biological marker for clinical monitoring of these patients. [Cancer Res 2007;67(4):1415–8
Insulin-like Growth Factor-1 (IGF-1) Induces WISP-2/CCN5 via Multiple Molecular Cross-talks and Is Essential for Mitogenic Switch by IGF-1 Axis in Estrogen Receptor–Positive Breast Tumor Cells
Authors: Dhar Kakali , Banerjee Snigdha , Dhar Gopal , Sengupta Krishanu , Banerjee Sushanta K. 
Published: February 2007

Abstract
Previously, we have shown that the expression of Wnt-1–induced signaling protein-2 (WISP-2), also known as CCN5, can be regulated by multiple stimulants in estrogen receptor (ER)–positive breast tumor cells to exert their mitogenic action in these cells. Here, we show that insulin-like growth factor-1 (IGF-1), a strong mitogen, enhanced the expression of the WISP-2/CCN5 gene parallel with the induction of proliferation of ER-positive breast tumor cells. An additive effect was also seen in combination with estrogen. Perturbation of IGF-1–induced WISP-2/CCN5 expression by WISP-2–specific RNA interference impaired the mitogenic action of IGF-1 on ER-positive breast tumor cells. Furthermore, the studies have shown that the multiple molecular cross-talks and side-talks among IGF-1R, ER-α, and phosphatidylinositol 3-kinase (PI3K)/Akt signaling molecules are required to induce WISP-2/CCN5 mRNA by IGF-1 in ER-positive, noninvasive breast tumor cells. Because a pure anti-ER ICI 182,780 is not only able to suppress the up-regulation of WISP-2/CCN5 mRNA expression by IGF-1, it also suppresses the PI3K/Akt activity induced by IGF-1 in MCF-7 cells; we anticipate that the membrane ER receptor may participate in this event. Collectively, these studies propose for the first time that WISP-2/CCN5 is an integral signaling molecule in mitogenic action of IGF-1 axis in ER-positive human breast tumor cells. [Cancer Res 2007;67(4):1520–6]
Antibody-Mediated p53 Protein Therapy Prevents Liver MetastasisIn vivo
Authors: Hansen James E. , Fischer Laurice K. , Chan Grace , Chang Sophia S. , Baldwin Scott W. , Aragon Robert J. , Carter Jacqueline J. , Lilly Michael , Nishimura Robert N. , Weisbart Richard H. , Reeves Mark E. 
Published: February 2007

AbstractTo evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated p53 protein therapy, an Fv-p53 fusion protein produced in Pichia pastoris was tested on CT26.CL25 colon cancer cells in vitro and in vivo in a mouse model of colon cancer metastasis to the liver. In vitro experiments showed killing of CT26.CL25 cells by Fv-p53 but not Fv or p53 alone, and immunohistochemical staining confirmed that Fv was required for transport of p53 into cells. Prevention of liver metastasis in vivo was tested by splenic injection of 100 nmol/L Fv-p53 10 min and 1 week after injection of CT26.CL25 cancer cells into the portal vein of BALB/c mice. Mice were sacrificed 1 week after the second injection of Fv-p53 and assigned a quantitative metastasis score. Control mice had an average metastasis score of 3.3 ± 1.3, whereas mice treated with Fv-p53 had an average metastasis score of 0.8 ± 0.4 (P = 0.004). These results indicate that Fv-p53 treatment had a profound effect on liver metastasis and represent the first demonstration of effective full-length p53 protein therapy in vivo. mAb 3E10 Fv has significant clinical potential as a mediator of intracellular and intranuclear delivery of p53 for prevention and treatment of cancer metastasis. [Cancer Res 2007;67(4):1769–74]
Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression
Authors: Iiizumi Megumi , Bandyopadhyay Sucharita , Watabe Kounosuke 
Published: February 2007

AbstractTumor metastases suppressor protein KAI1/CD82 is capable of blocking the tumor metastases without affecting the primary tumor formation, and its expression is significantly down-regulated in many types of human cancers. However, the exact molecular mechanism of the suppressor function of KAI1 remains elusive. Evidence from our laboratory supports a model in which tumor cells dislodge from the primary tumor and intravasate into the blood or lymphatic vessels followed by attachment to the endothelial cell surface whereby KAI1 interacts with the Duffy antigen receptor for chemokines (DARC) protein. This interaction transmits a senescent signal to cancer cells expressing KAI1, whereas cells that lost KAI1 expression can proliferate, potentially giving rise to metastases. Our model of the mechanism of action of KAI1 shows that metastasis suppressor activity can be dependent on interaction with host tissue and explains how KAI1 suppresses metastasis without affecting primary tumor formation. Taken together, in vitro and in vivo studies identify the KAI1-DARC interaction as a potential target for cancer therapy. [Cancer Res 2007;67(4):1411–4]
Genetic Unmasking of an Epigenetically Silenced microRNA in Human Cancer Cells
Authors: Lujambio Amaia , Ropero Santiago , Ballestar Esteban , Fraga Mario F. , Cerrato Celia , Setién Fernando , Casado Sara , Suarez-Gauthier Ana , Sanchez-Cespedes Montserrat , Gitt Anna , Spiteri Inmaculada , Das Partha P. , Caldas Carlos , Miska Eric , Esteller Manel 
Published: February 2007

Abstract
The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can “hit” miRNAs in transformed cells. To address this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells. One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene. [Cancer Res 2007;67(4):1424–9]
A Role for the HOXB7 Homeodomain Protein in DNA Repair
Authors: Rubin Ethel , Wu Xinyan , Zhu Tao , Cheung Joyce C.Y. , Chen Hexin , Lorincz Annaka , Pandita Raj K. , Sharma Girdhar G. , Ha Hyo Chol , Gasson Judith , Hanakahi Les A. , Pandita Tej K. , Sukumar Saraswati 
Published: February 2007

Abstract
Homeobox genes encode transcription factors which function in body axis patterning in the developing embryo. Recent evidence suggests that the maintenance of specific HOX expression patterns is necessary for regulating the homeostasis of adult tissues as well. In this study, HOXB7 transformed human mammary epithelial cells, MCF10A, to grow in minimally supplemented medium, to form colonies in Matrigel, and display resistance to ionizing radiation. Searching for protein partners of HOXB7 that might contribute to resistance to ionizing radiation, we identified four HOXB7-binding proteins by GST pull-down/affinity chromatography and confirmed their interactions by coimmunoprecipitation in vivo. Interestingly, all four HOXB7-binding proteins shared functions as genomic caretakers and included members of the DNA-dependent protein kinase holoenzyme (Ku70, Ku80, DNA-PKcs) responsible for DNA double-strand break repair by nonhomologous end joining pathway and poly(ADP) ribose polymerase. Exogenous and endogenous expression of HOXB7 enhanced nonhomologous end joining and DNA repair functions in vitro and in vivo, which were reversed by silencing HOXB7. This is the first mechanistic study providing definitive evidence for the involvement of any HOX protein in DNA double-strand break repair. [Cancer Res 2007;67(4):1527–35]
The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery
Authors: Smith Nicola F. , Raynaud Florence I. , Workman Paul 
Published: February 2007

Abstract
Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the ‘hit-to-lead’ and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage. [Mol Cancer Ther 2007;6(2):428–40]
Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor κB
Authors: Son Dong Ju , Park Mi Hee , Chae Sang Jin , Moon Soon Ok , Lee Jae Woong , Song Ho Sueb , Moon Dong Cheul , Kang Sang Sun , Kwon Young Ee , Hong Jin Tae 
Published: February 2007

Abstract
We investigated whether the snake venom toxin (SVT) from Vipera lebetina turanica inhibits cell growth of human prostate cancer cells by inducing apoptosis and also studied possible signaling pathways involved in this cell death. SVT inhibited growth of PC-3 and DU145 cells, androgen-independent prostate cancer cells, but not LNCaP cells, a human androgen-dependent prostate cancer cell. Cells were arrested in the G2-M phase by SVT with a concomitant decrease in the expression of the G2-M phase regulatory protein cyclin B1 and were also arrested in the G1-S phase with decreasing expression of cyclin-dependent kinase 4, cyclin D1 and cyclin E. In addition to the growth-inhibitory effect, SVT increased the induction of apoptotic cell death. Untreated PC-3 cells show high DNA binding activity of nuclear factor κB (NF-κB), an antiapoptotic transcriptional factor, but this was inhibited by SVT and accompanied by a significant inhibition of p50 translocation into the nucleus, as well as phosphorylation of inhibitory κB. Consistent with the induction of apoptosis and inhibition of NF-κB, this toxin increased the expression of proapoptotic proteins such as p53, Bax, caspase-3, and caspase-9, but down-regulated antiapoptotic protein Bcl-2. However, SVT did not show an inhibitory effect on cell growth and caspase-3 activity in cells carrying mutant p50 and inhibitory κB kinase plasmids. Confocal microscopy analysis showed that SVT is taken up into the nucleus of the cells. These findings suggest that a nanogram concentration range of SVT from V. lebetina turanica could inhibit hormone-refractory human prostate cancer cell growth, and the effect may be related to NF-κB signal–mediated induction of apoptosis. [Mol Cancer Ther 2007;6(2):675–83]