Abstract:
:Unlike the growth factor dependence of normal cells, cancer cells can maintain growth factor-independent glycolysis and survival through expression of oncogenic kinases, such as BCR-Abl. Although targeted kinase inhibition can promote cancer cell death, therapeutic resistance develops frequently, and further mechanistic understanding is needed. Cell metabolism may be central to this cell death pathway, as we have shown that growth factor deprivation leads to decreased glycolysis that promotes apoptosis via p53 activation and induction of the proapoptotic protein Puma. Here, we extend these findings to show that elevated glucose metabolism, characteristic of cancer cells, can suppress protein kinase Cδ (PKCδ)-dependent p53 activation to maintain cell survival after growth factor withdrawal. In contrast, DNA damage-induced p53 activation was PKCδ independent and was not metabolically sensitive. Both stresses required p53 Ser(18) phosphorylation for maximal activity but led to unique patterns of p53 target gene expression, showing distinct activation and response pathways for p53 that were differentially regulated by metabolism. Consistent with oncogenic kinases acting to replace growth factors, treatment of BCR-Abl-expressing cells with the kinase inhibitor imatinib led to reduced metabolism and p53- and Puma-dependent cell death. Accordingly, maintenance of glucose uptake inhibited p53 activation and promoted imatinib resistance. Furthermore, inhibition of glycolysis enhanced imatinib sensitivity in BCR-Abl-expressing cells with wild-type p53 but had little effect on p53-null cells. These data show that distinct pathways regulate p53 after DNA damage and metabolic stress and that inhibiting glucose metabolism may enhance the efficacy of and overcome resistance to targeted molecular cancer therapies.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Mason EF,Zhao Y,Goraksha-Hicks P,Coloff JL,Gannon H,Jones SN,Rathmell JCdoi
10.1158/0008-5472.CAN-10-0608subject
Has Abstractpub_date
2010-10-15 00:00:00pages
8066-76issue
20eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-0608journal_volume
70pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Her...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-10-3342
更新日期:2011-06-01 00:00:00
abstract::Previous studies have shown dose-dependent growth inhibition of the human mammary carcinoma cell line MDA-MB-231 xenotransplanted in athymic mice using retinol. In this study, the growth inhibitory effect of retinoic acid (RA) and 13-cis-retinoic acid (13-cis-RA) was examined in vitro and in vivo. With both agents the...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::Integrin alpha(5)beta(1) is overexpressed on endothelial cells of tumor vessels and is uniformly and rapidly accessible to antibodies in the bloodstream. Here, we determined whether antibodies rapidly gain access to integrin overexpressed on the abluminal (basolateral) surface of endothelial cells through vascular lea...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-2691
更新日期:2005-04-01 00:00:00
abstract::Defects in cell cycle control and increased genomic instability, including gene amplification, often occur during cancer development. Cyclin D1 plays a pivotal role in G1, and this gene is frequently amplified and overexpressed in several types of human cancer. This study demonstrates that ectopic overexpression of cy...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1996-01-01 00:00:00
abstract::We demonstrate that a mouse-human chimeric anti-ganglioside GD2-interleukin (IL)-2 fusion protein (ch14.18-IL2) substantially amplifies tumor-protective immunity against murine melanoma induced by an autologous oral DNA vaccine containing the murine ubiquitin gene fused to murine melanoma peptide epitopes gp100(25-35)...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-08-15 00:00:00
abstract::Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Here we demonstrate that in human pro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-03-15 00:00:00
abstract::7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that is under development as an anticancer agent in the United States and Japan. Long-term exposure of human A549 non-small cell lung cancer cells to UCN-01 furnished cells (A549/UCN) with acquired resistance against UCN-01. In this study, the sensitivity o...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1999-09-01 00:00:00
abstract::We have investigated the ability of several drugs commonly used in the treatment of human cancer to induce bcl2 phosphorylation and cell death in human cell lines derived from acute leukemia, lymphoma, breast cancer, and prostate cancer. The results of this analysis indicate that drugs affecting the integrity of micro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-01-15 00:00:00
abstract::It has been reported that HLA-DR is a potent inducer of thrombin generation. Human colorectal cells (GEO, WiDr, DLD-1, and MIP) that lack the constitutive expression of HLA-DR cause platelet aggregation through a thrombin-dependent mechanism. Treatment with recombinant human gamma-interferon induced the expression of ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::In contrast to methotrexate (MTX) and aminopterin (AMT), the 8-deaza analogues of these antifolates are not substrates for rabbit liver aldehyde oxidase. Since they are not converted to 7-hydroxy derivatives, they have been investigated with regard to their cytotoxicity for CCRF-CEM cells, transport into these cells, ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-03-15 00:00:00
abstract::Native chromosomal structure, breakage, and overall degradation were studied following the reaction of whole cells with the anticancer drug bleomycin and structurally related phleomycin. Electrophoretic analyses of cellular DNA established that phleomycin was more reactive with DNA than equimolar bleomycin in the rang...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::Epidemiological studies provide evidence that environmental factors (external agents such as chemicals, radiation, and viruses) play a major role in the causation of the majority of human tumors. This is a highly optimistic message, since it implies that cancer is largely a preventable disease. To meet this challenge ...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1988-08-01 00:00:00
abstract::Primary solid tumors were mechanically and/or enzymatically disassociated, and the resulting suspensions of single cells and small clumps of cells were seeded onto three different substrates, i.e., tissue culture plastic, rat smooth muscle cells (SMCs), and SMC-derived extracellular matrix. Tests of the relative effec...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
abstract::HeLa cells were synchronized at the G1-S boundary by double thymidine block and treated for 1 hr with varying concentrations of the antibiotic anticancer protein neocarzinostatin (NCS). Cells were then released from the block and allowed to resume their cycle. Aliquots were removed at various times in order to monitor...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1980-07-01 00:00:00
abstract::We identified DD3(PCA3) as one of the most prostate cancer-specific genes at present (M. J. Bussemakers et al. Cancer Res., 59: 5975-5979, 1999). Consequently, DD3(PCA3) is an interesting candidate for use as a diagnostic and/or prognostic marker. In this study we developed a method for the accurate quantification of ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-05-01 00:00:00
abstract::Adult rat parenchymal hepatocytes in primary culture can be induced to enter into DNA synthesis and mitosis. The optimal conditions for hepatocyte replication are low plating density (less than 10,000 cells/sq cm) and 50% serum from two-thirds partially hepatectomized rats (48 hr after hepatectomy). Approximately 80% ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1982-11-01 00:00:00
abstract::Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-ac...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-10-01 00:00:00
abstract::DNA methylation was measured in human tumor cell lines and freshly explanted pediatric tumors by [3H]uridine labeling followed by DNA hydrolysis and high-performance liquid chromatography. The percentage of cytosine residues modified to 5-methylcytosine in 4 cell lines derived from pediatric tumors was increased or si...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-10-01 00:00:00
abstract::We have established and characterized a diploid cell strain of normal human endothelial cells, RuBa 7E. RuBa 7E cells have an average cloning efficiency of 20% during early passages and undergo approximately 50 doublings in vitro before senescing spontaneously. At confluence, RuBa 7E cells form a homogeneous monolayer...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-03-01 00:00:00
abstract::Steroid sulfatase (STS) hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate. In the present study, we have measured STS mRNA levels in 97 breast cancers by reverse transcription-PCR using a fluorescent primer in the presence of an internal standard RNA ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1999-01-15 00:00:00
abstract::Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major adult liver cancers. The existence of combined hepatocellular-cholangiocarcinoma (CHC), a histopathologic intermediate form between HCC and CC, suggests phenotypic overlap between these tumors. Here, we applied an integrative oncogenomic approach...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-2823
更新日期:2010-04-15 00:00:00
abstract::Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non-small cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strat...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-3990
更新日期:2012-08-01 00:00:00
abstract::In a search for the molecular basis of ABH status of tumors as correlated with malignancy, we studied various malignancy-related phenotypes of high H/Le(y)-expressing tumor cell lines in comparison with phenotypes of the same lines transfected with histo-blood group A or B genes. A and B gene transfectants, prepared i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-08-01 00:00:00
abstract::Phosphorylation of heat shock protein 27 (HSP27) has been suggested to play an important role in the regulation of F-actin dynamics in response to growth factors and stress. Because the microfilament network is one of the earliest targets of oxidative stress and because phosphorylation of HSP27 is strongly induced by ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1996-01-15 00:00:00
abstract::Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortunately, a major side effect of the taxanes and Vinca alkaloids is the developme...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-1342
更新日期:2009-01-01 00:00:00
abstract::DNA synthesis was studied in mouse ascites sarcoma cells using a permeable cell system. The sarcoma was induced by the Schmidt-Ruppin strain of Rous sarcoma virus. The cells were made permeable to nucleoside triphosphates by treatment with a hypotonic buffer containing 10 mM Tris Cl, 4 mM MgCl2, 1 mM EDTA, and 6 mM 2-...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-01-01 00:00:00
abstract::In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patie...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-11-0367
更新日期:2011-08-15 00:00:00
abstract::In the present study, we assessed the susceptibility of freshly isolated neuroblastoma cells to killing mediated by normal human natural killer (NK) cells and analyzed the receptor-ligand interactions that regulate this event. We show that killing of freshly isolated neuroblasts, similar to neuroblastoma cell lines, i...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-2682
更新日期:2004-12-15 00:00:00
abstract::Myeloproliferative disorders (MPD) are stem cell-derived clonal diseases arising as a consequence of acquired aberrations in c-ABL, Janus-activated kinase 2 (JAK2), and platelet-derived growth factor receptor (PDGFR) that generate oncogenic fusion tyrosine kinases (FTK), including BCR/ABL, TEL/ABL, TEL/JAK2, and TEL/P...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-1101
更新日期:2008-09-01 00:00:00
abstract::N,N-Dimethylformamide treatment of cell cultures established from a transplantable murine rhabdomyosarcoma-induced morphological differentiation and a marked reduction in the tumorigenicity of the sarcoma cells. Fourteen of 17 CE/J mice receiving injections of inducer-treated cells did not develop tumors after 6 month...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-09-01 00:00:00