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1.
Survivin is a member of the inhibitor of apoptosis protein family that is overexpressed in various tumors and is important
in restricting apoptosis. Understanding the molecular events of apoptosis may provide information for developing novel therapeutic
agents targeting non-small cell lung cancer (NSCLCs). This study used three human NSCLC cell lines, NCI-H1299, SK-MES-1, and
NCI-H460. Changes in apoptosis, the mRNA and protein expression of survivin under normoxia and hypoxia, with or without rapamycin
treatment were analyzed. In addition, siRNA and ChIP assay were further applied to demonstrate the role of hypoxia-inducible
factor 1 (HIF-1)α in regulating survivin expression regulation under hypoxia during rapamycin induced NSCLC cell apoptosis. Treatment with
rapamycin resulted in significantly increased NSCLC cells apoptosis under hypoxia. We demonstrated for the first time that
rapamycin inhibited hypoxia-induced survivin expression in NSCLC cell lines. We further demonstrated that HIF-1α participated in hypoxia-induced survivin expression, and that rapamycin inhibited hypoxia-induced HIF-1α expression by enhancing its degradation. The results above collectively showed that rapamycin inhibits HIF-1α-induced survivin expression under hypoxia to induce NSCLC apoptosis. 相似文献
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Guo M Song LP Jiang Y Liu W Yu Y Chen GQ 《Apoptosis : an international journal on programmed cell death》2006,11(1):67-77
Hypoxia presents pro-apoptotic and anti-apoptotic biphasic effects that appear to be dependent upon cell types and conditions
around cells. The substantial reports demonstrated that commonly used hypoxia-mimetic agents cobalt chloride (CoCl2) and desferrioxamine (DFO) could also induce apoptosis in many different kinds of cells, but the mechanism was poorly understood.
In this work, we compare the apoptosis-inducing effects of these two hypoxia-mimetic agents with acute myeloid leukemic cell
lines NB4 and U937 as in vitro models. The results show that both of them induce these leukemic cells to undergo apoptosis with a loss of mitochondrial
transmembrane potentials (ΔΨ m), the activation of caspase-3/8 and the cleavage of anti-apoptotic protein Mcl-1, together
with the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein, a critical regulator for the cellular response
to hypoxia. Metavanadate and sodium nitroprusside significantly abrogate DFO rather than CoCl2-induced mitochondrial Δ Ψ m collapse, caspase-3/8 activation, Mcl-1 cleavage and apoptosis, but they fail to influence DFO
and CoCl2-induced HIF-1α protein accumulation. Moreover, inducible expression of HIF-1α gene dose not alter DFO and CoCl2-induced apoptosis in U937 cells. In conclusion, these results propose that although both DFO and CoCl2-induced leukemic cell apoptosis by mitochondrial pathway-dependent and HIF-1α-independent mechanisms, DFO and CoCl2-induced apoptosis involves different initiating signal pathways that remain to be investigated. 相似文献
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Multidrug resistance (MDR) is a significant problem underlying the poor prognosis associated with gliomas. Hypoxia-inducible
factor-1α (HIF-1α) is thought to induce the genes expression involved in MDR. To evaluate the effect of silencing HIF-1α in
human glioma T98G cells, cells were transfected with HIF-1α-small interference RNA (HIF-1α-siRNA) and cultured under hypoxic
conditions. The effect of HIF-1α-siRNA on HIF-1α and multidrug resistance-associated protein 1 gene (MRP1) and protein levels
was determined. Silencing rates of HIF-1α were 90%, 85%, and 88% at 24, 48, 72 h post-transfection, respectively. Corresponding
rates of HIF-1α protein were 74.5%, 61.1% and 59.1%. MRP1 protein levels decreased by 7.6%, 36.8% and 45.2%. HIF-1α-siRNA
transfected cells were significantly more sensitive to doxorubicin and etoposide compared to non-transfected cells. These
findings suggest that the HIF-1α plays a role in mediating chemotherapeutic drug resistance in glioma cells. HIF-1α silencing
may prove to be an effective therapeutic means of treating gliomas. 相似文献
8.
Stefan K. Alig Yvonn Stampnik Joachim Pircher Raffaela Rotter Erik Gaitzsch Andrea Ribeiro Markus W?rnle Florian Kr?tz Hanna Mannell 《PloS one》2015,10(3)
Introduction
The tyrosine phosphatase SHP-1 negatively influences endothelial function, such as VEGF signaling and reactive oxygen species (ROS) formation, and has been shown to influence angiogenesis during tissue ischemia. In ischemic tissues, hypoxia induced angiogenesis is crucial for restoring oxygen supply. However, the exact mechanism how SHP-1 affects endothelial function during ischemia or hypoxia remains unclear. We performed in vitro endothelial cell culture experiments to characterize the role of SHP-1 during hypoxia.Results
SHP-1 knock-down by specific antisense oligodesoxynucleotides (AS-Odn) increased cell growth as well as VEGF synthesis and secretion during 24 hours of hypoxia compared to control AS-Odn. This was prevented by HIF-1α inhibition (echinomycin and apigenin). SHP-1 knock-down as well as overexpression of a catalytically inactive SHP-1 (SHP-1 CS) further enhanced HIF-1α protein levels, whereas overexpression of a constitutively active SHP-1 (SHP-1 E74A) resulted in decreased HIF-1α levels during hypoxia, compared to wildtype SHP-1. Proteasome inhibition (MG132) returned HIF-1α levels to control or wildtype levels respectively in these cells. SHP-1 silencing did not alter HIF-1α mRNA levels. Finally, under hypoxic conditions SHP-1 knock-down enhanced intracellular endothelial reactive oxygen species (ROS) formation, as measured by oxidation of H2-DCF and DHE fluorescence.Conclusions
SHP-1 decreases half-life of HIF-1α under hypoxic conditions resulting in decreased cell growth due to diminished VEGF synthesis and secretion. The regulatory effect of SHP-1 on HIF-1α stability may be mediated by inhibition of endothelial ROS formation stabilizing HIF-1α protein. These findings highlight the importance of SHP-1 in hypoxic signaling and its potential as therapeutic target in ischemic diseases. 相似文献9.
Sollid J Rissanen E Tranberg HK Thorstensen T Vuori KA Nikinmaa M Nilsson GE 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2006,176(4):359-369
Hypoxia inducible factor 1 alpha (HIF-1α) initiates expression of a wide variety of genes, some of which are involved in apoptosis
and cell cycle arrest. We have previously shown that crucian carp increases its respiratory surface area 7.5-fold in response
to hypoxia. This change is due to apoptosis and cell cycle arrest in specific parts of its gills. Here we have characterized
crucian carp HIF-1α, and measured mRNA, protein and DNA binding levels during hypoxia exposure in crucian carp gills. We have
also measured an HIF-1α-induced gene, the inducible nitric oxide synthase (iNOS), which has the ability to initiate apoptosis
and cell cycle arrest. Crucian carp HIF-1α was found to have all critical domains known to be important for function. Comparison
of the peptide sequence with other species indicated high similarity with other cyprinid fish, but a pronounced variation
compared to the salmonid, rainbow trout. Further, we found HIF-1α protein to be stabilized during hypoxia. Further, HIF-1α
was often present in normoxia, and showed marked individual weight-dependent variation. We found no alteration of iNOS mRNA
levels during hypoxia exposure. These findings suggest HIF-1α involvement in hypoxia-induced change of respiratory surface
area in crucian carp gills. However, its activity does not seem to be mediated through iNOS. 相似文献
10.
Tomokazu Tanaka Yoshihiko Kitajima Shuusuke Miyake Kazuyoshi Yanagihara Hiromitsu Hara Aki Nishijima-Matsunobu Koichi Baba Masaaki Shida Kota Wakiyama Jun Nakamura Hirokazu Noshiro 《PloS one》2015,10(9)
Gastric cancer grows under a hypoxic environment. HIF-1α is known to play an important role in controlling the production of reactive oxygen species (ROS) in the mitochondria under hypoxic conditions. We previously established HIF-1α knockdown (KD) cells and control (SC) cells in the 58As9 gastric cancer cell line. In this study, we revealed that KD cells, but not SC cells, induced apoptosis under conditions of hypoxia (1% O2) due to excessive production of ROS. A quantitative RT-PCR analysis demonstrated that the expressions of ten genes, which are involved in the control mechanisms of ROS (including the Warburg effect, mitophagy, electron transport chain [ETC] modification and ROS scavenging), were regulated by HIF-1α. Moreover, the promotion of glucose uptake by glucose plus insulin (GI) treatment enhanced the apoptotic effect, which was accompanied by further ROS production in hypoxic KD cells. A Western blot analysis showed that the membranous expression of GLUT1 in KD cells was elevated by glucose and/or insulin treatments, indicating that the GI-induced glucose uptake is mediated by the increased translocation of GLUT1 on the cell membrane. Finally, the anti-tumor effect of HIF-1α knockdown (KD) plus GI was evaluated using a tumor xenograft model, where a hypoxic environment naturally exists. As a result, the GI treatment strongly inhibited the growth of the KD tumors whereby cell apoptosis was highly induced in comparison to the control treatment. In contrast, the growth of the SC tumors expressing HIF-1α was not affected by the GI treatment. Taken together, the results suggest that HIF-1α inhibition plus GI may be an ideal therapy, because the apoptosis due to the destruction of ROS homeostasis is specifically induced in gastric cancer that grows under a hypoxic environment, but not in the normal tissue under the aerobic conditions. 相似文献
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Lubomir Prochazka Lan-Feng Dong Karel Valis Ruth Freeman Stephen J. Ralph Jaroslav Turanek Jiri Neuzil 《Apoptosis : an international journal on programmed cell death》2010,15(7):782-794
Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation
of reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been clearly
defined. In this study with the mitocan α-tocopheryl succinate (α-TOS) the role of the Bcl-2 family proteins in the mechanism
of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to α-TOS increased expression
of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was independent of the cellular p53
status. α-TOS caused a profound conformational change in the pro-apoptotic protein, Bak, involving oligomerization in all
cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer cells. Immunoprecipitation studies
indicated that α-TOS activates the two BH1-3 proteins, Bak or Bax, to form high molecular weight complexes in the mitochondria.
RNAi knockdown revealed that Noxa and Bak are required for α-TOS-induced apoptosis, and the role of Bak was confirmed using
Bak- and/or Bax-deficient cells. We conclude that the major events induced by α-TOS in cancer cells downstream of ROS production
leading to mitochondrial apoptosis involve the Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial
destabilization activated by a variety of mitocans that induce accumulation of ROS in the early phases of apoptosis. 相似文献
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Jawahir M Nicholas SA Coughlan K Sumbayev VV 《Apoptosis : an international journal on programmed cell death》2008,13(12):1410-1416
Nitric oxide (NO) is a reactive secondary mediator, which has been found to participate in cell cycle regulation and apoptosis
in myeloid macrophages, the key effectors of inflammatory and innate immune responses. However, the molecular mechanisms of
nitric oxide-induced death of myeloid macrophages are not well understood. In this study we have found that NO derived from
S-nitrosoglutathione (GSNO) activates ASK1 in THP-1 human myeloid macrophages in a concentration and time-dependent manner.
It also induces accumulation of HIF-1α protein in a concentration-dependent manner, which peaks at 4 h of exposure to 1 mM
GSNO. GSNO does not affect the level of HIF-1α mRNA as detected by the RT-PCR. In addition, GSNO was found to induce accumulation
of p53 in normal but not HIF-1α knockdown THP-1 cells, where expression of this protein was silenced by specific siRNA. It
has also been found that GSNO-mediated accumulation of p53 depends on activation of ASK1 since no GSNO-induced p53 stabilisation
was observed in THP-1 cells transfected with dominant-negative form of this kinase. However, in both HIF-1α knockdown THP-1
cells and those transfected with the dominant-negative form of ASK1, GSNO was able to induce cell death as detected by the
MTS cell viability assay leading to an increase in release of LDH. 相似文献
15.
Recent studies suggest a novel role of HIF-1α under non-hypoxic conditions, including antibacterial and antiviral innate immune
responses. However, the identity of the pathogen-associated molecular pattern which triggers HIF-1α activation during the
antiviral response remains to be identified. Here, we demonstrate that cellular administration of double-stranded nucleic
acids, the molecular mimics of viral genomes, results in the induction of HIF-1α protein level as well as the increase in
HIF-1α target gene expression. Whole-genome DNA microarray analysis revealed that double-stranded nucleic acid treatment triggers
induction of a number of hypoxia-inducible genes, and induction of these genes are compromised upon siRNA-mediated HIF-1α
knock-down. Interestingly, HIF-1α knock-down also resulted in down-regulation of a number of genes involved in antiviral innate
immune responses. Our study demonstrates that HIF-1α activation upon nucleic acid-triggered antiviral innate immune responses
plays an important role in regulation of genes involved in not only hypoxic response, but also immune response.
These authors contributed equally to this work. 相似文献
16.
Hwang JM Weng YJ Lin JA Bau DT Ko FY Tsai FJ Tsai CH Wu CH Lin PC Huang CY Kuo WW 《Molecular and cellular biochemistry》2008,311(1-2):179-187
Chronic cardiac ischemia/hypoxia induces coronary collateral formation and cardiomyocyte proliferation. Hypoxia can induce
cellular adaptive responses, such as synthesis of VEGF for angiogenesis and IGF-2 for proliferation. Both reduce apoptotic
effects to minimize injury or damage. To investigate the mechanism of neoangiogenesis and proliferation of fetal heart under
umbilical cord compression situation, we used H9c2 cardiomyoblast cell culture, and in vivo embryonic hearts as our study
models. Results showed hypoxia induced not only the increase of IGF-2 and VEGF expression but also the activation of their
upstream regulatory genes, HIF-1α and Shh. The relationship between HIF-1α and Shh was further studied by using cyclopamine
and 2-ME2, inhibitor of Shh and HIF-1α signaling, respectively, in the cardiomyoblast cell culture under hypoxia. We found
that the two inhibitors not only blocked their own signal pathway, but also inhibited each other. The observations revealed
when fetal heart under hypoxia that HIF-1α and Shh pathways maybe involve in cell proliferation and neoangiogenesis to minimize
injury or damage, whereas the complex cross-talk between the two pathways remains unknown.
Pei-Cheng Lin, Chih-Yang Huang, and Wei-Wen Kuo contributed equally to this work. 相似文献
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Zheng Y Shi X Wang M Jia Y Li B Zhang Y Liu Q Wang Y 《Molecular biology reports》2012,39(4):4229-4236
Overexpression of differentiated embryo chondrocyte 1 (DEC1) has been reported to contribute to the cellular differentiation,
proliferation, and apoptosis of various cancers. Our previous studies have shown that DEC1 was highly expressed in gastric
cancer (GCa) tissues. However, there is no report about the expression of DEC1 in GCa cell lines until now. In this study,
We evaluated the mRNA and protein expression of DEC1 and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions
in six GCa cell lines: BGC-823, MGC80-3, MKN1, AGS, FU97 and SGC-7901. An HIF-1α protein inhibitor was used to analyze the
association of DEC1 and HIF-1α expression. Under normoxia, the mRNA expression of both HIF-1α and DEC1 was moderate, whereas
the protein expression of DEC1 was higher than that of HIF-1α. Hypoxia induced the mRNA expression of DEC1 and the protein
expression of HIF-1α and DEC1 in a time-dependent manner but had no effect on the mRNA expression of HIF-1α. Furthermore,
inhibition of HIF-1α protein expression resulted in a significant decrease in both the mRNA and protein expression of DEC1.
Taken together, DEC1 expression is correlated with HIF-1α protein in GCa cell line, blockage of HIF-1α protein led to reduced
DEC1 expression. The efficacy of inhibiting HIF-1α and DEC1 expression should be tested in clinical trials as possible treatment
for GCa. 相似文献
19.
Nevzglyadova OV Artyomov AV Mikhailova EV Soidla TR 《Molecular genetics and genomics : MGG》2005,274(4):419-427
It has been shown that defects in cell fusion during mating can trigger programmed cell death in the yeast Saccharomyces cerevisiae. We wished to test whether defects in nuclear migration during cell fusion have the same effect. A partial pedigree analysis
of nine kar1 × KAR1 crosses of two different types (four α KAR1 × a
kar1 and five α kar1 × a
KAR1 crosses) was carried out, and quantitative estimates of the frequencies of different mother/daughter (m/d) classes were obtained.
The kar1 mutation affects nuclear congression and delays nuclear fusion. In each cross tested, the nucleus that entered the first
bud tended to be the one contributed by the cell that carried the wild-type allele of KAR1. If budding was delayed by nutrient limitation, the kar1 nucleus could be rescued, indicating that the primary effect of the kar1 mutation is that it slows spindle action. Many m/d classes appear as a result of the degradation of one of the nuclei in
the heterokaryon. Loss of nuclei in heterokaryons was accompanied by an accumulation of reactive oxygen species (ROS), and
by abnormalities in nuclear structure revealed by TUNEL (terminal transferase-mediated dUTP nick end-labeling) analysis, DAPI
staining and by histone-GFP fluorescence patterns which suggested an apoptosis-like process. Often only one nucleus was degraded,
and ROS accumulation was restricted to one half of the zygote. We therefore suggest that the data obtained can be explained
by apoptosis-like death of a half-cell (cell body). 相似文献
20.
Xiang ZL Zeng ZC Fan J Tang ZY He J Zeng HY Chang JY 《Molecular biology reports》2012,39(2):2021-2029
The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression
in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with
external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary
HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the
Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical
regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic
LN EBRT response. Kaplan–Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression
model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = −0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence
interval (CI): 0.499–0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509–0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531–0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those
with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression
in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis. 相似文献