Abstract:
:Resistance of pancreatic cancer to current treatments including radiotherapy remains a major challenge in oncology and may be caused by defects in apoptosis programs. Since 'inhibitor of apoptosis proteins' (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could tackle a key resistance mechanism. Here, we report that targeting X-linked inhibitor of apoptosis (XIAP) by RNA-interference-mediated knockdown or overexpression of second mitochondria-derived activator of caspase significantly enhanced apoptosis and markedly reduced clonogenic growth of pancreatic carcinoma cells upon gamma-irradiation. Analysis of signaling pathways revealed that antagonizing XIAP increased activation of caspase-2, -3, -8 and -9 and loss of mitochondrial membrane potential upon gamma-irradiation. Interestingly, inhibition of caspases also reduced the cooperative effect of XIAP targeting and gamma-irradiation to trigger mitochondrial perturbations, suggesting that XIAP controls a feedback mitochondrial amplification loop by regulating caspase activity. Importantly, our data demonstrate for the first time that small molecule XIAP inhibitors sensitized pancreatic carcinoma cells for gamma-irradiation-induced apoptosis, whereas they had no effect on gamma-irradiation-mediated apoptosis of non-malignant fibroblasts indicating some tumor specificity. In conclusion, targeting XIAP, for example by small molecules, is a promising novel approach to enhance radiosensitivity of pancreatic cancer that warrants further investigation.
journal_name
Oncogenejournal_title
Oncogeneauthors
Giagkousiklidis S,Vellanki SH,Debatin KM,Fulda Sdoi
10.1038/sj.onc.1210502subject
Has Abstractpub_date
2007-10-25 00:00:00pages
7006-16issue
49eissn
0950-9232issn
1476-5594pii
1210502journal_volume
26pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-017-0047-5
更新日期:2018-03-01 00:00:00
abstract::We identified the chromosome 11q23 region as containing a putative tumour suppressor gene(s) frequently deleted in nonfamilial breast and other cancers. To define this region(s) further, we performed a systematic genetic analysis at chromosome 11q14-qterm in sporadic breast and colorectal cancer. Tumour and constituti...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1200847
更新日期:1997-01-30 00:00:00
abstract::In the childhood cancer neuroblastoma (NB), the level of expression of the multidrug resistance-associated protein (MRP1) gene is strongly correlated with expression of the MYCN oncogene in primary NB tumors, suggesting that MRP1 may be a target for MYCN-mediated gene regulation. In this study, we show that MYCN induc...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1207151
更新日期:2004-01-22 00:00:00
abstract::Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interferenc...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210625
更新日期:2008-01-03 00:00:00
abstract::Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a tumor suppressor that catalyzes the de-phosphorylation of the AGC kinases, while p27 acts as a tumor suppressor that regulates cell cycle, apoptosis, and cell motility. Our previous studies have identified that PHLPP2 participates in in...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-018-0374-1
更新日期:2018-10-01 00:00:00
abstract::Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an onco...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.465
更新日期:2016-08-04 00:00:00
abstract::Pretreatment of cells with 0.5 mM sodium arsenite (but not other activators of stress-activated MAP kinase cascades) prevents the activation of p21Ras and strongly suppresses the activation of c-Raf and the MAP kinase cascade by a variety of growth factors. Arsenite appears to exert its effect by preventing the guanin...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202168
更新日期:1998-07-09 00:00:00
abstract::The product of the proto-oncogene fos is a nuclear phosphoprotein. We have investigated if nuclear location of Fos protein is mediated by a nuclear targeting sequence. We show that the cytoplasmic chicken pyruvate kinase protein translocates to the nucleus if fused to the 22 amino acid Fos basic region (amino acids 13...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1991-11-01 00:00:00
abstract::Melanoma progression is typically depicted as a linear and stepwise process in which metastasis occurs relatively late in disease progression. Significant evidence suggests that in a subset of melanomas, progression is much more complex and less linear in nature. Epidemiologic and experimental observations in melanoma...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2013.194
更新日期:2014-05-08 00:00:00
abstract::Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-R1 and TRAIL-R2 gene...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1204103
更新日期:2001-01-18 00:00:00
abstract::The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that tran...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208597
更新日期:2005-06-16 00:00:00
abstract::The plasma membrane-associated tyrosine phosphatase PTPRO is frequently transcriptionally repressed in cancers and signifies poor prognosis of breast cancer patients. In this study, deletion of Ptpro in MMTV-Erbb2 transgenic mice dramatically shortened the mammary tumor latency and accelerated tumor growth due to loss...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2016.213
更新日期:2017-01-19 00:00:00
abstract::Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. Previous research suggests that inhibition of topoII decatenatory activity triggers a G(2) checkpoint response, which delays mitotic entry because of insuffici...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2010.232
更新日期:2010-08-26 00:00:00
abstract::Mammalian nuclear Dbf2-related (NDR) kinases (LATS1 and 2, NDR1 and 2) play a role in cell proliferation, apoptosis and morphological changes. These kinases are regulated by mammalian sterile 20-like kinases (MSTs) and Mps one binder (MOB) 1. Okadaic acid (OA), which activates MST2, facilitates the complex formation o...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2008.66
更新日期:2008-07-17 00:00:00
abstract::Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-1256-x
更新日期:2020-05-01 00:00:00
abstract::Mammalian target of rapamycin complex (mTORC) regulates a variety of cellular responses including proliferation, growth, differentiation and cell migration. In this study, we show that mammalian target of rapamycin complex 2 (mTORC2) regulates invasive cancer cell migration through selective activation of Akt1. Insuli...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2011.22
更新日期:2011-06-30 00:00:00
abstract::Activation of the Akt/PKB protein kinase family triggers increases in cell size, metabolism and survival. Akt coordinately regulates these fundamental cellular processes through phosphorylation-dependent inactivation of tumor suppressors and activation of trophic signaling. Akt signaling stimulates transport and metab...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1209097
更新日期:2005-11-14 00:00:00
abstract::Dual specificity kinases that phosphorylate the Thr- and Tyr-residues within the TXY motif of MAP-kinases of play a central role in the regulation of various processes of cell growth. These dual specificity kinases also known as MAP kinase kinases are constituents of the sequential kinase signaling modules. Seven dist...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1202251
更新日期:1998-09-17 00:00:00
abstract::Rearrangements of the NFKB2 gene are associated with lymphoid malignancies, but the functional significance of these alterations is not known. Here we characterize structurally and functionally a rearranged NFKB2 gene identified at the T cell lymphoma line, HUT78. The rearrangement has truncated NFKB2 sequences within...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1994-07-01 00:00:00
abstract::Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed new light on the involvement of a class of noncoding RNA known as microRNA (miRNA) in gastric cancer. A substantial number of miRNAs show ...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2010.352
更新日期:2010-10-28 00:00:00
abstract::The initiation, magnitude and duration of an immune response against antigens are a tightly regulated process involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is critical for allowing efficient immune response against foreign antigens while preve...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2009.334
更新日期:2010-01-14 00:00:00
abstract::ID4 gene is a member of the inhibitor of DNA-binding (ID) family, which inhibits DNA binding of basic helix-loop-helix transcription factors. Certain human primary breast cancers reportedly have low or no expression of ID4 protein, but its role in carcinogenesis and cancer progression is unknown. To determine its poss...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208538
更新日期:2005-07-07 00:00:00
abstract::The p53 protein is a multifunctional transcription factor which orchestrates cellular responses to DNA damage, so helping to conserve genomic stability. It may also regulate genes involved in intercellular signalling, such as thrombospondin, a negative regulator of angiogenesis and metastatic spread. Activation of p53...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-08-17 00:00:00
abstract::This report describes a new polymorphism, in intron 3 of the p53 gene, which consists of a single repeat of 16 nucleotides, absent in the published wild-type p53 gene sequence. In the Caucasian population tested (n = 82), 28% of individuals were heterozygotes for this polymorphism. Using PCR-based analysis, we were ab...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1993-06-01 00:00:00
abstract::Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differenc...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1205330
更新日期:2002-04-11 00:00:00
abstract::Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein-Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 rec...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208367
更新日期:2005-03-03 00:00:00
abstract::In previous studies examining the role of pp60c-src in cellular proliferation, we demonstrated that overexpression of wild type (wt) but not mutated c-src in C3H10T1/2 murine embryo fibroblasts resulted in a 2 to 5 fold enhancement of DNA synthesis in response to epidermal growth factor (EGF). Using phosphotyrosine an...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
abstract::SAP-1 (stomach cancer-associated protein tyrosine phosphatase-1) is a transmembrane-type protein tyrosine phosphatase that has been implicated as a negative regulator of integrin-mediated signaling. The potential role of this enzyme in hepatocarcinogenesis has now been investigated by examining its expression in 32 su...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206588
更新日期:2003-07-24 00:00:00
abstract::While studying Bim, a BH3-only proapoptotic protein, we identified an approximately 36 kDa protein, which was abundantly expressed in all five strains of primary normal human prostate (NHP) epithelial cells but significantly reduced or lost in seven prostate cancer cell lines. The approximately 36 kDa protein was subs...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1206196
更新日期:2003-03-13 00:00:00
abstract::Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally expos...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.243
更新日期:2016-04-14 00:00:00