Abstract:
:MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Lin JJ,Milhollen MA,Smith PG,Narayanan U,Dutta Adoi
10.1158/0008-5472.CAN-10-2062subject
Has Abstractpub_date
2010-12-15 00:00:00pages
10310-20issue
24eissn
0008-5472issn
1538-7445pii
70/24/10310journal_volume
70pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::Low income, poor diet, obesity, and a lack of exercise are interrelated lifestyle factors that can profoundly alter our biologic make up to increase cancer risk, growth, and development. We recently reported a potential mechanistic link between carbohydrate-derived metabolites and cancer, which may provide a biologic ...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:10.1158/0008-5472.CAN-15-0169
更新日期:2015-05-15 00:00:00
abstract::We report the chromosomal characteristics of a recurrent pineal non-seminomatous germ cell tumor in a 16-year-old male patient. This non-seminomatous tumor had the following components: embryonal carcinoma, teratoma, yolk sac tumor, and trophoblastic giant cells. Chromosome analysis showed a near-triploid karyotype (6...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-03-15 00:00:00
abstract::Malignant undifferentiated sarcomas were induced in 11 of 15 (73.3%) newborn Syrian hamsters by s.c. inoculation of a recombinant DNA (pBK/c-rasA) containing BK virus (BKV) early region gene and the activated human c-Harvey-ras(c-Ha-ras) oncogene derived from T24 bladder carcinoma. The two genes inoculated independent...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-12-15 00:00:00
abstract::Prostate-specific membrane antigen (PSMA) is highly expressed by both normal and malignant prostate epithelial cells and by the neovasculature of many tumor types; however, it is not expressed by normal endothelial cells or other normal tissues. PSMA, therefore, represents an attractive candidate for selectively targe...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-1520
更新日期:2006-09-15 00:00:00
abstract::The local growth rate of Morris Hepatoma 44 (generation time, 6 months) was inhibited by 66 to 87%, and host survival was prolonged by 36 to 78% after the induction of hypothyroidism within 2 weeks of tumor implantation by propylthiouracil (0.1% in Purina chow), 131I(1 mCi/100 g body weight i.p.), or surgical thyroide...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-08-01 00:00:00
abstract::In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vei...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-11-01 00:00:00
abstract::Tumorigenic activities of the (+)- and (-)-enantiomers of the diastereomeric, bay-region benzo(c)phenanthrene 3,4-diol-1,2-epoxides were evaluated in two mouse tumor models. In an initiation-promotion experiment on mouse skin, a single topical application of 10, 25, or 75 nmol of the compounds was followed by 20 weeks...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-05-01 00:00:00
abstract::Although aberrant microRNA (miRNA) is expressed in different types of human cancer tissues, its pathophysiologic role and the relevance of tumorigenesis and metastasis are still largely unknown. Here, we defined miRNAs involved in cancer metastasis (metastamirs) using an established mouse model for peritoneal dissemin...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-10-2530
更新日期:2011-02-15 00:00:00
abstract::The occurrence of spontaneous skin papillomas in Japanese newts (Cynops pyrrhogaster) from Niigata prefecture in Northern Japan was monitored over four seasons covering a period of 2 years. Of 13,613 newts, 249 were found to possess papillomas. The percentage of newts with papillomas was highest in autumn, ranging fro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1982-09-01 00:00:00
abstract::Our laboratory has found genomic imprinting of a large genomic domain of human 11p15.5, identifying six imprinted genes within this domain: (a) insulin-like growth factor II (IGF-II), an important autocrine growth factor in a wide variety of malignancies; (b) H19, an untranslated RNA that is a putative growth suppress...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1999-04-01 00:00:00
abstract::PE-35 mouse monoclonal antibody (MoAb) (IgG1) detecting an epithelial antigen with a molecular weight of 35,000 was characterized serologically. Immunoperoxidase staining and double immunoenzymatic staining showed that PE-35 antigen is predominantly on nonlymphoid cells in the medulla of thymus. By immunoelectron micr...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-04-01 00:00:00
abstract::Wnt ligand-driven tumor growth is inhibited by the soluble Wnt inhibitor Fzd8CRD, but the mechanism through which this effect is mediated is unknown. In the MMTV-Wnt1 mouse model, regression of mammary tumors by Fzd8CRD treatment coincides with an acute and strong induction of insulin-like growth factor (IGF)-binding ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-3668
更新日期:2012-03-15 00:00:00
abstract::The effects of sodium butyrate, dimethyl sulfoxide (DMSO), and retinoic acid on the growth, morphology, carcinoembryonic antigen content, cell surface membrane-associated enzyme activities, and glycoprotein profiles of a human rectal adenocarcinoma cell line (HRT-18) in culture were compared. All three agents reversib...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::Recent work has begun to explore the instrumental role that small noncoding RNA species, particularly microRNAs (miRNA), have both in classifying human tumors and in directing embryonic development. These studies suggest that developmental programs in essentially all organisms studied are set, in part, by varied expre...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-1894
更新日期:2006-11-15 00:00:00
abstract::The anticarcinogenic activities of retinoic acid (RA) are believed to be mediated by the nuclear RA receptor (RAR) and by the RA-binding protein cellular RA-binding protein-II (CRABP-II). In MCF-7 mammary carcinoma cells, growth inhibition by RA entails an early cell cycle arrest followed by induction of apoptosis. He...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0989
更新日期:2007-01-15 00:00:00
abstract::In order to test the contention that metastasis is a selective process and that therefore metastases might show a more restricted pattern of phenotypic and genotypic characteristics than primary tumors, we compared the expression of carcinoembryonic antigen, Ca 19-9, secretory component, serotonin, and mucin productio...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-08-15 00:00:00
abstract::Molecular insights into how chronic stress affects lung tumorigenesis may offer new routes to chemoprevention. In this study, we show that chronic stress in mice chemically or genetically initiated for lung cancer leads to the release of norepinephrine and other catecholamines, thereby promoting lung tumorigenesis. Me...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-16-0990
更新日期:2016-11-15 00:00:00
abstract::High-grade gliomas are characterized by exuberant vascularization, diffuse invasion, and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate in the long term. Targeting protumoral signals in the glioma microenvironment could have significant impact against tumor cell...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-0685
更新日期:2014-10-01 00:00:00
abstract::Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides....
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-3096
更新日期:2005-06-01 00:00:00
abstract::The antitumor activity of IFN-alpha is well established. However, the role of the plasmacytoid dendritic cell (PDC), the major producer of IFN-alpha upon viral infection, in tumor biology is unknown. We sought to study the presence and function of PDC in a human solid tumor. Here, we demonstrate that PDCs infiltrate t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-10-01 00:00:00
abstract::Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-2471
更新日期:2007-09-01 00:00:00
abstract::The relationship between coffee drinking and the risk of digestive tract neoplasms was analyzed in a case-control study of 50 cases of cancer of the mouth or pharynx, 209 of the esophagus, 397 of the stomach, 455 of the colon, 295 of the rectum, 151 of the liver, 214 of the pancreas, and 1944 control subjects admitted...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-02-15 00:00:00
abstract::A recent pilot study that we performed on 12 individuals who are involved in the cultivation and processing of grains and legumes suggests to us that we may have in hand a relatively quick, inexpensive, and highly sensitive assay that identifies individuals at increased risk for the development of lymphoid malignancy....
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1992-10-01 00:00:00
abstract::Tumor-derived cell lines are used as in vitro cancer models, but their ability to accurately reflect the phenotype and genotype of the parental histology remains questionable, given the prevalence of documented cell line-specific cytogenetic changes. We have addressed the issue of whether copy number alterations seen ...
journal_title:Cancer research
pub_type: 杂志文章,meta分析
doi:10.1158/0008-5472.CAN-06-3674
更新日期:2007-04-15 00:00:00
abstract::The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling netwo...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-3358
更新日期:2016-01-15 00:00:00
abstract::The amount of iododeoxyuridine (IdUrd) incorporated into DNA determines the degree of radiosensitization. Fluorodeoxyuridine (FdUrd) has been shown to biochemically modulate IdUrd incorporation into DNA in vitro and in vivo. In this Phase I study, these drugs were coadministered to patients during 14-day continuous i....
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-05-15 00:00:00
abstract::Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. Although astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here, we demonstrate that astrocy...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-17-1463
更新日期:2017-12-01 00:00:00
abstract::The effects of various forms of tocopherol (vitamin E) on the growth and differentiation of mouse melanoma (B-16) and mouse fibroblast (L-cells) cells in culture were studied. D-alpha-tocopherol acid succinate induced morphological alterations and growth inhibition in melanoma cells. When vitamin E acid succinate was ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1982-02-01 00:00:00
abstract::The notion that nuclear factor-kappaB (NF-kappaB) is a tumor-promoting transcription factor has become a widely accepted dogma in biology. However, recent findings suggest an inhibitory role for NF-kappaB in carcinogenesis and tumorigenesis. Although the tumor suppressor-like effect of NF-kappaB remains to be rigorous...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:10.1158/0008-5472.CAN-07-1576
更新日期:2007-12-01 00:00:00
abstract::Patients with longstanding extensive ulcerative colitis have an increased risk of developing colorectal cancer (CRC). There are significant differences in the early pathogenesis of colitis-associated tumors compared with common CRC, whereas the frequency, degree, and significance of microsatellite instability (MSI) as...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-04-01 00:00:00