Abstract:
:The microenvironment of rapidly growing tumors is associated with increased energy demand and diminished vascular supply, resulting in focal areas of prominent hypoxia. A number of hypoxia-responsive genes have been associated with growing tumors, and here we demonstrate that the multidrug resistance (MDR1) gene product P-glycoprotein, a Mr approximately 170,000 transmembrane protein associated with tumor resistance to chemotherapeutics, is induced by ambient hypoxia. Initial studies using quantitative microarray analysis of RNA revealed an approximately 7-fold increase in MDR in epithelial cells exposed to hypoxia (pO(2) 20 torr, 18 h). These findings were further confirmed at the mRNA and protein level. P-Glycoprotein function was studied by analysis of verapamil-inhibitable efflux of digoxin and rhodamine 123 in intact T84 cells and revealed that hypoxia enhances P-glycoprotein function by as much as 7 +/- 0.4-fold over normoxia. Subsequent studies confirmed hypoxia-elicited MDR1 gene induction and increased P-glycoprotein expression in nontransformed, primary cultures of human microvascular endothelial cells, and analysis of multicellular spheroids subjected to hypoxia revealed increased resistance to doxorubicin. Examination of the MDR1 gene identified a binding site for hypoxia inducible factor-1 (HIF-1), and inhibition of HIF-1 expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible MDR1 expression and a nearly complete loss of basal MDR1 expression. Studies using luciferase promoter constructs revealed a significant increase in activity in cells subjected to hypoxia, and such hypoxia inducibility was lost in truncated constructs lacking the HIF-1 site and in HIF-1 binding site mutants. Extensions of these studies also identified a role for Sp1 in this hypoxia response. Taken together, these data indicate that the MDR1 gene is hypoxia responsive, and such results may identify hypoxia-elicited P-glycoprotein expression as a pathway for resistance of some tumors to chemotherapeutics.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Comerford KM,Wallace TJ,Karhausen J,Louis NA,Montalto MC,Colgan SPsubject
Has Abstractpub_date
2002-06-15 00:00:00pages
3387-94issue
12eissn
0008-5472issn
1538-7445journal_volume
62pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by intera...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0522
更新日期:2007-03-15 00:00:00
abstract::In an attempt to approach the mechanism by which estrogen and antiestrogen regulate the growth of estrogen receptor-positive breast cancer, we have studied the effects of the antiestrogens tamoxifen (TAM) and 4-hydroxytamoxifen (OH-TAM) on the induction of two estrogen-specific proteins in a variant of MCF7 cells term...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-05-01 00:00:00
abstract::Our previous study showed that spleen cells from BALB/c mice bearing RL male 1 lymphoma inhibited the growth of RL male 1 lymphoma by the Winn-type adoptive transfer assay. Although this antitumor activity was mediated by the T-cell subset manifesting the surface phenotype of cytotoxic T-lymphocytes (CTLs), this antit...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::Proliferating mammalian stem and cancer cells express telomerase [telomerase reverse transcriptase (TERT)] in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA-binding protein SSB1, which has a critical role in DNA dou...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-2289
更新日期:2015-03-01 00:00:00
abstract::The initiation-promotion model for the production of skin tumors in mice has proven useful for studying the influence of nutritional variations on stages in neoplasia. Specifically, restriction in caloric intake or fat level in the diet as well as a supplemental retinoid protect against tumor promotion. In contrast, t...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1983-05-01 00:00:00
abstract::Interleukin 15 (IL-15) is a novel cytokine that shares no homology with IL-2, but it requires the use of beta and gamma chains of the IL-2 receptor complex for binding and signaling. In vitro studies have shown induction of CTL and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acq...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-07-15 00:00:00
abstract::Human polymorphic N-acetyltransferase (NAT2) catalyzes the N-acetylation of arylamine carcinogens and the metabolic activation of N-hydroxyarylamine and N-hydroxyarylamide carcinogens by O- and N,O-acetylation, respectively. Rapid and slow acetylator phenotype is regulated at the NAT2 locus, and each has been associat...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-08-15 00:00:00
abstract::Evaluation of a large panel of radiation-induced rat skin tumors of diverse size and histological type revealed a correlation between c-myc copy number and tumor size. Both the frequency and degree of c-myc gene amplification were increased in large compared to small carcinomas, but none of the sarcomas examined showe...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1990-05-15 00:00:00
abstract::Using JM and MOLT3, two human T-cell acute lymphoblastic leukemia cell lines, we investigated the ability of 24-h thymidine exposures to enhance the cytotoxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin). Clinically achievable thymidine concentrations (for 24 h) significantly enhanced c...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-11-01 00:00:00
abstract::The regulation of cyclic adenosine 3:5-monophosphate (cyclic AMP) phosphodiesterase activity in homogenates of malignant and cyclic AMP-induced "differentiated" neuroblastoma cells was studied. Neuroblastoma cells of at least three mouse and one human clone had both the low (2 to 4 muM) and the high (66 to 106 muM) Km...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1975-01-01 00:00:00
abstract::The complement system is important in immunosurveillance against tumors. However, malignant cells are usually resistant to complement-mediated lysis. In this study, we examine the expression of factor H, an inhibitor of complement activation, and factor H-like protein 1 (FHL-1), its alternatively spliced form, in lung...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-03-2328
更新日期:2004-09-01 00:00:00
abstract::The BCR/ABL fusion protein is a constitutively active tyrosine kinase that is responsible for the pathogenesis of chronic myelogenous leukemia (CML). Clinically, CML is characterized by a chronic phase (CP) that eventually terminates into a blast crisis (BC). BC transformation is associated with accumulation of CD34+ ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-02-01 00:00:00
abstract::Glycerol and D2O can provide a protective effect to Chinese hamster V79 cells receiving heat treatment. The mechanism for this effect is assumed to be the ability of these agents to stabilize proteins which implies that one of the possible heat-killing mechanisms is the inactivation of a heat-sensitive molecule (prote...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-12-01 00:00:00
abstract::Analyses of losses of heterozygosity and linkage studies have implicated a gene(s) on chromosome 17q in the genesis of sporadic and early-onset familial breast carcinomas, respectively. To define the critical region of 17q, we examined DNAs from a series of 20 sporadic breast carcinomas and corresponding blood samples...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::Several metabolic processes, such as DNA organization and replication, transcription, and RNA processing are closely associated with the nuclear matrix. Nuclear matrix attachment regions are nucleotide sequences holding DNA tightly complexed with the nuclear scaffold and are resistant to extractions with detergents an...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-09-01 00:00:00
abstract::Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a...
journal_title:Cancer research
pub_type: 评论,杂志文章
doi:10.1158/0008-5472.CAN-19-2060
更新日期:2020-02-15 00:00:00
abstract::Current awareness of the importance of environmental factors such as diet in the etiology of human cancer has stimulated renewed interest in animal models for studying effects of diet on tumorigenesis. Diet can influence cancer in animals by affecting the initiation or subsequent preneoplastic stage of tumorigenesis, ...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1975-11-01 00:00:00
abstract::Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breas...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-2150
更新日期:2014-12-01 00:00:00
abstract::Human B-cell lymphomas are frequently associated with specific genetic changes caused by chromosomal translocations that activate proto-oncogenes. For lymphomas of mice expressing murine leukemia virus, mutagenic proviral insertions are thought to play a similar role. Here we report studies designed to determine wheth...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-03-3885
更新日期:2004-07-01 00:00:00
abstract::In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have previously shown that certain flavonoids inhibit in vitro angiogenesis. Here, we show that the flavonoid luteolin inhibited tumor growth and angiogenesis in a m...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-03-3104
更新日期:2004-11-01 00:00:00
abstract::Capan 1, a human pancreatic cancer cell line, is routinely grown in 10% fetal calf serum (FCS). In order to characterize the factors needed for its proliferation, FCS was replaced by a synthetic serum (Ultroser G). For Capan 1 proliferation we found that Ultroser G was as efficient as FCS. A subfraction of Ultroser G ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-07-15 00:00:00
abstract::(-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenol in green tea, has been shown to inhibit the growth of many cancer cell lines and to suppress the phosphorylation of epidermal growth factor receptor (EGFR). We observed similar effects of EGCG in esophageal squamous cell carcinoma KYSE 150 cells and epide...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-0480
更新日期:2005-09-01 00:00:00
abstract::The development of a supportive vasculature is essential for tumor progression. In a mouse model of breast cancer, we found that tumor-associated macrophages that are recruited to the tumor just before malignant conversion are essential for the angiogenic switch. These findings establish a causal linkage to explain we...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-0912
更新日期:2007-06-01 00:00:00
abstract::MicroRNAs (miRNA) are negative regulators of gene expression at the posttranscriptional level, which are involved in tumorigenesis. Two miRNAs, miR-15a and miR-16, which are located at chromosome 13q14, have been implicated in cell cycle control and apoptosis, but little information is available about their role in so...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-4277
更新日期:2009-07-01 00:00:00
abstract::To investigate the relationship between serum micronutrients and the subsequent risk of oral and pharyngeal cancer, a nested case-control study was conducted within a cohort of 25,802 adults in Washington County, MD, whose blood samples were collected in 1974 and stored at -70 degrees C for subsequent assays. The seru...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1993-02-15 00:00:00
abstract::The mechanism of latent membrane protein LMP1 of EBV in inducing cell transformation and tumorigenesis was investigated in Rat-1 fibroblasts. A plasmid encoding a site-specific mutant of LMP1 defective in binding to tumor necrosis factor receptor-associated death domain protein was constructed. This LMP1(TRADD) gene i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-04-01 00:00:00
abstract::Sensitivities to sister chromatid exchange (SCE) induction by chemicals of peripheral lymphocytes from 26 cancer patients were estimated under conditions identical to those for healthy humans which had been reported (Cancer Res., 43: 439-442, 1983). The sensitive individual was defined as one whose cells give a mean i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-02-01 00:00:00
abstract::Cancer cells commonly display aberrant surface glycans and related glycoconjugate scaffolds. Compared with their normal counterparts, cancer cell glycans are variably produced and often structurally distinct, serving as biomarkers of cancer progression or as functional entities to malignancy. The glycan signature of a...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:10.1158/0008-5472.CAN-15-0834
更新日期:2015-08-15 00:00:00
abstract::The genetic alterations that occur during esophageal tumorigenesis have yet to be determined. We previously established a Wister rat carcinogenesis model of esophageal squamous cell carcinoma. To understand more about the molecular mechanisms during carcinogenesis, we produced esophageal neoplastic lesions by administ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2005-01-15 00:00:00