bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor-α Blocks Apoptosis in Melanoma Cells when BRAF Signaling Is Inhibited
Authors: Gray-Schopfer Vanessa C. , Karasarides Maria , Hayward Robert , Marais Richard 
Published: January 2007

Abstract
The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in ∼70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-α. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-α and BRAF interaction because TNF-α does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-κB (NF-κB) transcription factor activity, which is strongly induced by TNF-α in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-α and/or NF-κB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma. [Cancer Res 2007;67(1):122–9]
Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine Depletion
Authors: Cheng Paul Ning-Man , Lam Tin-Lun , Lam Wai-Man , Tsui Sam-Mui , Cheng Anthony Wai-Ming , Lo Wai-Hung , Leung Yun-Chung 
Published: January 2007

Abstract
Hepatocellular carcinoma (HCC) is believed to be auxotrophic for arginine through the lack of expression of argininosuccinate synthetase (ASS). The successful use of the arginine-depleting enzyme arginine deiminase (ADI) to treat ASS-deficient tumors has opened up new possibilities for effective cancer therapy. Nevertheless, many ASS-positive HCC cell lines are found to be resistant to ADI treatment, although most require arginine for proliferation. Thus far, an arginine-depleting enzyme for killing ASS-positive tumors has not been reported. Here, we provide direct evidence that recombinant human arginase (rhArg) inhibits ASS-positive HCCs. All the five human HCC cell lines we used were sensitive to rhArg but ADI had virtually no effect on these cells. They all expressed ASS, but not ornithine transcarbamylase (OTC), the enzyme that converts ornithine, the product of degradation of arginine with rhArg, to citrulline, which is converted back to arginine via ASS. Transfection of HCC cells with OTC resulted in resistance to rhArg. Thus, OTC expression alone may be sufficient to induce rhArg resistance in ASS-positive HCC cells. This surprising correlation between the lack of OTC expression and sensitivity of ASS-positive HCC cells shows that OTC-deficient HCCs are sensitive to rhArg-mediated arginine depletion. Therefore, pretreatment tumor gene expression profiling of ASS and OTC could aid in predicting tumor response to arginine depletion with arginine-depleting enzymes. We have also shown that the rhArg native enzyme and the pegylated rhArg (rhArg-peg5,000mw) gave similar anticancer efficacy in vitro. Furthermore, the growth of the OTC-deficient Hep3B tumor cells (ASS-positive and ADI-resistant) in mice was inhibited by treatment with rhArg-peg5,000mw, which is active alone and is synergistic in combination with 5-fluorouracil. Thus, our data suggest that rhArg-peg5,000mw is a novel agent for effective cancer therapy. [Cancer Res 2007;67(1):309–17]
[177Lu]Pertuzumab: Experimental Therapy of HER-2–Expressing Xenografts
Authors: Persson Mikael , Gedda Lars , Lundqvist Hans , Tolmachev Vladimir , Nordgren Hans , Malmström Per-Uno , Carlsson Jörgen 
Published: January 2007

Abstract
Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy β emitter 177Lu, might be a candidate for targeted radiotherapy of disseminated HER-2–positive micrometastases. The radiolabeled antibody [177Lu]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2–overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [177Lu]pertuzumab delayed tumor progression compared with controls (no treatment, P &lt; 0.0001; nonlabeled pertuzumab antibody, P &lt; 0.0001; and 177Lu-labeled irrelevant antibody, P &lt; 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [177Lu]pertuzumab for therapy. [Cancer Res 2007;67(1):326–31]
Potentiation of Kinesin Spindle Protein Inhibitor–Induced Cell Death by Modulation of Mitochondrial and Death Receptor Apoptotic Pathways
Authors: Vijapurkar Ulka , Wang Wei , Herbst Ronald 
Published: January 2007

Abstract
Targeting the mitotic motor kinesin kinesin spindle protein (KSP) is a new strategy for cancer therapy. We have examined the molecular events induced by KSP inhibition and explored possible mechanisms of resistance and sensitization of tumor cells to KSP inhibitors. We found that KSP inhibition induced cell death primarily via activation of the mitochondrial death pathway. In HeLa cells, inhibition of KSP by small-molecule inhibitor monastrol resulted in mitotic arrest and rapid caspase activation. BclXL phosphorylation and loss of mitochondrial membrane potential was detected before significant caspase activation, which was required to trigger the subsequent apoptotic pathway. In A549 cells, however, KSP inhibition did not induce mitochondrial damage, significant caspase activity, or cell death. A549 cells aberrantly exited mitosis, following a prolonged drug-induced arrest, and arrested in a G1-like state with 4N DNA content in a p53-dependent manner. Overexpression of BclXL provided a protective mechanism, and its depletion rescued the apoptotic response to monastrol. In addition, Fas receptor was up-regulated in A549 cells in response to monastrol. Treatment with Fas receptor agonists sensitized the cells to monastrol-induced cell death, following exit from mitosis. Thus, activation of the death receptor pathway offered another mechanism to enhance KSP inhibitor–induced apoptosis. This study has elucidated cellular responses induced by KSP inhibitors, and the results provide insights for a more effective cancer treatment with these agents. [Cancer Res 2007;67(1):237–45]
Aberrant Splicing of Cyclin-Dependent Kinase–Associated Protein Phosphatase KAP Increases Proliferation and Migration in Glioblastoma
Authors: Yu Yi , Jiang Xiuli , Schoch Brad S. , Carroll Rona S. , Black Peter M. , Johnson Mark D. 
Published: January 2007

Abstract
The cyclin-dependent kinase (Cdk)–associated protein phosphatase KAP is a dual-specificity phosphatase of which the only known function is to dephosphorylate Cdk2 and inhibit cell cycle progression. Paradoxically, we find increased KAP mRNA expression in malignant astrocytomas, which correlates with increasing histologic grade and decreased patient survival. We have resolved this apparent paradox with the discovery of aberrant KAP splicing in malignant astrocytomas that leads to increased expression of KAP-related transcripts but decreased KAP protein expression. In addition, the aberrant splicing generates a dominant negative KAP variant that increases proliferation. We provide the first evidence that KAP not only regulates proliferation but also inhibits migration by decreasing cdc2 mRNA and protein expression. The effect of KAP on cdc2 expression requires its phosphatase activity but does not involve direct dephosphorylation of cdc2. Thus, KAP regulates both cdc2-dependent migration and Cdk2-dependent proliferation, and its loss due to aberrant splicing increases malignancy in human gliomas. [Cancer Res 2006;67(1):130–8]
Mechanisms of Mitotic Cell Death Induced by Chemotherapy-Mediated G2 Checkpoint Abrogation
Authors: Vogel Celia , Hager Christian , Bastians Holger 
Published: January 2007

Abstract
The novel concept of anticancer treatment termed “G2 checkpoint abrogation” aims to target p53-deficient tumor cells and is currently explored in clinical trials. The anticancer drug UCN-01 is used to abrogate a DNA damage–induced G2 cell cycle arrest leading to mitotic entry and subsequent cell death, which is poorly defined as “mitotic cell death” or “mitotic catastrophe.” We show here that UCN-01 treatment results in a mitotic arrest that requires an active mitotic spindle checkpoint, involving the function of Mad2, Bub1, BubR1, Mps1, Aurora B, and survivin. During the mitotic arrest, hallmark parameters of the mitochondria-associated apoptosis pathway become activated. Interestingly, this apoptotic response requires the spindle checkpoint protein Mad2, suggesting a proapoptotic function for Mad2. However, although survivin and Aurora B are also required for the mitotic arrest, both proteins are part of an antiapoptotic pathway that restrains the UCN-01–induced apoptosis by promoting hyperphosphorylation of Bcl-2 and by inhibiting the activation of Bax. Consequently, inhibition of the antiapoptotic pathway by genetic ablation of survivin or by pharmacologic inhibitors of Aurora B or cyclin-dependent kinase 1 lead to a significant enhancement of apoptosis and therefore act synergistically with UCN-01. Thus, by defining the mechanism of cell death on G2 checkpoint abrogation we show a highly improved strategy for an anticancer treatment by the combined use of UCN-01 with abrogators of the survivin/Aurora B–dependent antiapoptotic pathway that retains the selectivity for p53-defective cancer cells. [Cancer Res 2007;67(1):339–45]
Induction of Human ArylamineN-Acetyltransferase Type I by Androgens in Human Prostate Cancer Cells
Authors: Butcher Neville J. , Tetlow Natasha L. , Cheung Catherine , Broadhurst Gysell M. , Minchin Rodney F. 
Published: January 2007

AbstractHuman arylamine N-acetyltransferases (NAT) bioactivate arylamine and heterocyclic amine carcinogens present in red meat and tobacco products. As a result, factors that regulate expression of NATs have the potential to modulate cancer risk in individuals exposed to these classes of carcinogens. Because epidemiologic studies have implicated well-done meat consumption as a risk factor for prostate cancer, we have investigated the effects of androgens on the expression of arylamine N-acetyltransferase type I (NAT1). We show that NAT1 activity is induced by R1881 in androgen receptor (AR)–positive prostate lines 22Rv1 and LNCaP, but not in the AR-negative PC-3, HK-293, or HeLa cells. The effect of R1881 was dose dependent, with an EC50 for R1881 of 1.6 nmol/L. Androgen up-regulation of NAT1 was prevented by the AR antagonist flutamide. Real-time PCR showed a significant increase in NAT1 mRNA levels for R1881-treated cells (6.60 ± 0.80) compared with vehicle-treated controls (1.53 ± 0.17), which was not due to a change in mRNA stability. The increase in NAT1 mRNA was attenuated by concurrent cycloheximide treatment, suggesting that the effect of R1881 may not be by direct transcriptional activation of NAT1. The dominant NAT1 transcript present following androgen treatment was type IIA, indicating transcriptional activation from the major NAT1 promoter P1. A series of luciferase reporter deletions mapped the androgen responsive motifs to a 157-bp region of P1 located 745 bases upstream of the first exon. These results show that human NAT1 is induced by androgens, which may have implications for cancer risk in individuals. [Cancer Res 2007;67(1):85–92]
Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue–Induced Damage
Authors: Belinsky Martin G. , Guo Ping , Lee Kun , Zhou Feng , Kotova Elena , Grinberg Alex , Westphal Heiner , Shchaveleva Irina , Klein-Szanto Andres , Gallo James M. , Kruh Gary D. 
Published: January 2007

Abstract
Nucleoside-based analogues are mainstays in the treatment of cancer, viral infections, and inflammatory diseases. Recent studies showing that the ATP-binding cassette transporter, multidrug resistance protein 4, is able to efflux nucleoside and nucleotide analogues from transfected cells suggests that the pump may affect the efficacy of this class of agents. However, the in vivo pharmacologic functions of the pump are largely unexplored. Here, using Mrp4−/− mice as a model system, and the nucleotide analogue, 9′-(2′-phosphonylmethoxyethyl)-adenine (PMEA) as a probe, we investigate the ability of Mrp4 to function in vivo as an endogenous resistance factor. In the absence of alterations in plasma PMEA levels, Mrp4-null mice treated with PMEA exhibit increased lethality associated with marked toxicity in several tissues. Affected tissues include the bone marrow, spleen, thymus, and gastrointestinal tract. In addition, PMEA penetration into the brain is increased in Mrp4−/− mice. These findings indicate that Mrp4 is an endogenous resistance factor, and that the pump may be a component of the blood-brain barrier for nucleoside-based analogues. This is the first demonstration that an ATP-binding cassette transporter can affect in vivo tissue sensitivity towards this class of agents. [Cancer Res 2007;67(1):262–8]
Bin1 Ablation in Mammary Gland Delays Tissue Remodeling and Drives Cancer Progression
Authors: Chang Mee Young , Boulden Janette , Sutanto-Ward Erika , Duhadaway James B. , Soler Alejandro Peralta , Muller Alexander J. , Prendergast George C. 
Published: January 2007

Abstract
Genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. The Bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of Myc. Bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly. In this study, we investigated the effects of mammary gland–specific deletion of Bin1 on initiation and progression of breast cancer in mice. Bin1 loss delayed the outgrowth and involution of the glandular ductal network during pregnancy but had no effect on tumor susceptibility. In contrast, in mice where tumors were initiated by the ras-activating carcinogen 7,12-dimethylbenz(a)anthracene, Bin1 loss strongly accentuated the formation of poorly differentiated tumors characterized by increased proliferation, survival, and motility. This effect was specific as Bin1 loss did not accentuate progression of tumors initiated by an overexpressed mouse mammary tumor virus-c-myc transgene, which on its own produced poorly differentiated and aggressive tumors. These findings suggest that Bin1 loss cooperates with ras activation to drive progression, establishing a role for Bin1 as a negative modifier of oncogenicity and progression in breast cancer. [Cancer Res 2007;67(1):100–7]
c-Jun NH2-Terminal Kinase 2 Is Required for Ras Transformation Independently of Activator Protein 1
Authors: Nielsen Christina , Thastrup Jacob , Bøttzauw Trine , Jäättelä Marja , Kallunki Tuula 
Published: January 2007

Abstract
Active Ras oncogene is expressed in ∼30% of human cancers. Yet, very little is known about the molecular mechanisms responsible for its transforming potential. Here, we show that H-Ras-mediated transformation requires isoform 2 of the c-Jun-NH2-terminal kinase (JNK). H-Ras-transduced JNK2-deficient (Jnk2−/−) murine embryonic fibroblasts (MEFs) were severely inhibited in colony formation and growth in soft agar in vitro as well as in tumor formation in immunodeficient mice as compared with corresponding Jnk1−/− and wild-type MEFs. Accordingly, the RNA interference–based depletion of JNK2 form wild-type MEFs also resulted in defective Ras transformation. The extra barrier against H-Ras transformation in Jnk2−/− MEFs was not due to their inability to inactivate p53 signaling because all JNK2-deficient MEF lines had lost p19Arf. Furthermore, expression of the E6 protein of the human papilloma virus failed to overcome the transformation defect. It could, however, be overcome by coexpression of H-Ras with the SV40 large T antigen or c-Myc. Surprisingly, the H-Ras-transduced JNK2-deficient MEFs exhibited higher activity of activator protein-1 and higher levels of c-Jun expression compared with H-Ras-transduced JNK1-deficient or wild-type cells, indicating that the key target of JNK2 during Ras transformation was divergent from activator protein-1. These results clearly show that a single kinase, JNK2, could control Ras transformation and thus point out a vulnerable control point that may prove important for the tumor development in general. [Cancer Res 2007;67(1):178–85]
Inhibition of Histone Deacetylation Does Not Block Resilencing of p16 after 5-Aza-2′-Deoxycytidine Treatment
Authors: Egger Gerda , Aparicio Ana M. , Escobar Sonia G. , Jones Peter A. 
Published: January 2007

Abstract
Epigenetic drugs are in use in clinical trials of various human cancers and are potent at reactivating genes silenced by DNA methylation and chromatin modifications. We report here the analysis of a set of normal fibroblast and cancer cell lines after combination treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) and the histone deacetylase inhibitor 4-phenylbutyric acid (PBA). Low doses of the drug combination caused cell cycle arrest, whereas high doses induced apoptosis in T24 bladder carcinoma cells. Both p16 (CDKN2A/INK4) and p21 (CIP1/SDI1/WAF1) expression were induced to similar levels in normal and cancer cells in a dose-dependent fashion after combination treatments. We detected a distinct increase of histone H3 acetylation at lysine 9/14 near the transcription start sites, in both LD419 normal fibroblasts and T24 bladder carcinoma cells, whereas the acetylation changes in the p21 locus were less apparent. Interestingly, the levels of trimethylation of histone H3 on lysine 9, which usually marks inactive chromatin regions and was associated with the p16 promoter in silenced T24 cells, did not change after drug treatments. Furthermore, we provide evidence that the remethylation of the p16 promoter CpG island in T24 cells after 5-aza-CdR treatment cannot be halted by subsequent continuous PBA treatment. The p16 gene is resilenced with kinetics similar to 5-aza-CdR only–treated cells, which is also marked by a localized loss of histone acetylation at the transcription start site. Altogether, our data provide new insights into the mechanism of epigenetic drugs and have important implications for epigenetic therapy. [Cancer Res 2007;67(1):346–53]
Transgenic Overexpression of RasGRP1 in Mouse Epidermis Results in Spontaneous Tumors of the Skin
Authors: Oki-Idouchi Carolyn E. , Lorenzo Patricia S. 
Published: January 2007

Abstract
RasGRP1 is a guanine nucleotide exchange factor for Ras and a receptor of the second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters. We have recently shown expression of RasGRP1 in the epidermal keratinocytes where it can mediate Ras activation in response to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, a well-known mouse skin tumor promoter. To explore the participation of RasGRP1 in skin carcinogenesis, we targeted the overexpression of RasGRP1 to basal epidermal keratinocytes using the keratin 5 promoter. These transgenic mice were viable and indistinguishable from their littermates, with normal differentiation and skin architecture. However, a percentage of the adult transgenic population developed spontaneous skin tumors, mainly squamous cell papillomas. The transgene was detected in the tumors as well as in primary keratinocytes isolated from transgenic mice. The transgenic keratinocytes also displayed elevated levels of active, GTP-loaded Ras compared with the levels observed in keratinocytes derived from wild-type littermates. We noticed a correlation between tumor incidence and wounding, which suggests that RasGRP1 overexpression may confer sensitivity to promotional stimuli, like wound repair mechanisms. Interestingly, we also found elevated levels of granulocyte colony-stimulating factor in conditioned media derived from transgenic keratinocytes subjected to in vitro wounding. Taken together, these data are the first to provide evidence of a novel role for RasGRP1 in skin carcinogenesis and suggest that RasGRP1 may participate in tumorigenesis through modulation of Ras and autocrine pathways. [Cancer Res 2007;67(1):276–80]
Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor–Dependent Hypoxia-Inducible Factor Stabilization
Authors: Winner Millicent , Koong Albert C. , Rendon Beatriz E. , Zundel Wayne , Mitchell Robert A. 
Published: January 2007

AbstractLow oxygen tension–mediated transcription by hypoxia-inducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1α expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor–induced HIF-1α stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1α. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1α interactions. This functional interdependence between HIF-1α and MIF may represent an important and previously unrecognized protumorigenic axis. [Cancer Res 2007;67(1):186–93]
Heterozygous Deletion of Mitotic Arrest–Deficient Protein 1 (MAD1) Increases the Incidence of Tumors in Mice
Authors: Iwanaga Yoichi , Chi Ya-Hui , Miyazato Akiko , Sheleg Sergey , Haller Kerstin , Peloponese Jean-Marie , Li Yan , Ward Jerrold M. , Benezra Robert , Jeang Kuan-Teh 
Published: January 2007

Abstract
Mitotic arrest–deficient protein 1 (MAD1) is a component of the mitotic spindle assembly checkpoint. We have created a knockout mouse model to examine the physiologic consequence of reduced MAD1 function. Mad1+/− mice were successfully generated, but repeated paired mating of Mad1+/− with Mad1+/− mice failed to produce a single Mad1−/− animal, suggesting that the latter genotype is embryonic lethal. In aging studies conducted for &gt;18 months, Mad1+/− mice compared with control wild-type (wt) littermates showed a 2-fold higher incidence of constitutive tumors. Moreover, 42% of Mad1+/− (P &lt; 0.03), but 0% of wt, mice developed neoplasia after treatment with vincristine, a microtubule depolymerization agent. Mad1+/− mouse embryonic fibroblasts (MEF) were found to be more prone than wt cells to become aneuploid; Mad1+/−, but not wt, MEFs produced fibrosarcomas when explanted into nude mice. Our results indicate an essential MAD1 function in mouse development and correlate Mad1 haploinsufficiency with increased constitutive tumors. [Cancer Res 2007;67(1):160–6]