Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

Erler, Janine T.; Cawthorne, Christopher; Williams, Kaye J.; Koritzinsky, Marianne; Wouters, Bradly G.; Wilson, Claire; Miller, Crispin; Demonacos, Constantinos; Stratford, Ian J.; Dive, Caroline

doi:10.1128/mcb.24.7.2875-2889.2004

Cited by 363 publications

(330 citation statements)

References 53 publications

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“…Similarly in human colon cells, changes of Bid expression level was considered to contribute to the chemoresistance under hypoxia. 34 Bax could also be upregulated under hypoxia in both HT1080 and HT1080-6TG cells with no major difference between HIF-1-silenced cells and their parent cells. Further research is warranted to validate the findings in this study.…”

Section: Discussionmentioning

confidence: 90%

“…Inhibition of glucose transport-1 expression and also drug resistancerelated proteins such as mdr1, mrp and lrp, and increased level of proapoptotic proteins such as Bid and Bax were ever reported to form the therapeutic basis of HIF-1 interference. 34,35 However, many factors might also limit the therapeutic efficacy of HIF-1 silencing. HIF-1a plays dual roles in the adaptive responses to hypoxia; 36,37 HIF-1 inhibition can have bimodal effects, proapoptotic or antiapoptotic, the relative dominance of which, together with environmental cues may ultimately determine the cell fate.…”

Section: Discussionmentioning

confidence: 99%

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Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Hao

Song

et al. 2008

Cancer Gene Ther

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Therapy targeting hypoxia-inducible factor-1 (HIF-1) to reverse the hypoxia-related drug resistance has received much interest. Despite a close interaction between HIF-1 and p53 and that p53 mutation is seen in 450% of tumors, whether HIF-1 silencing by targeted therapy depends on tumor p53 status remains unknown. Two isogenic fibrosarcoma cells HT1080 (wild-type p53) and HT1080-6TG (mutant p53) were transduced with HIF-1a-specific RNAi lentiviral vectors and selected with blasticidin. Real-time PCR and western blot analysis of HIF-1a mRNA and protein respectively validated the silencing effects. Cells were first preconditioned under hypoxia (0.5% O 2 ) for 4 h and then co-treated with cisplatin for another 24 h. MTT was used for assessment of chemosensitivity to cisplatin. Moreover, annexin V and propidium iodide staining was detected on flow cytometry for analysis of cisplatin-induced apoptosis. Furthermore, changes of some Bcl-2 family members were detected on western blotting. Exposure to hypoxia significantly increased resistance to cisplatin than exposure to normoxia. HIF-1a knockdown could reverse hypoxia-related resistance to cisplatin and apoptotic resistance only in HT1080 cells, but had little effect on HT1080-6TG cells. With HIF-1a knockdown, Bid expression was higher in HT1080 than in HT1080-6TG under hypoxia. In summary, HIF-1 targeted therapy to reverse hypoxia-related cisplatin resistance depends on normal p53 status. Changes of Bid expression levels under hypoxia might contribute in part to the differential response to HIF-1a silencing in cells with different p53 status.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Hao

Song

et al. 2008

Cancer Gene Ther

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“…The response to hypoxia has an imperative function in the pathogenesis of many diseases, as exemplified by ischemic disease following stroke or myocardial infarction, and in tumorigenesis (Semenza, 2001;Chandel and Simon, 2008). During tumor formation, large hypoxic regions are created, providing a strongly stressful microenvironment that selects for cells with increased capacity for both metastasis and resistance to cell death (Rofstad, 2000;Brown and Wilson, 2004;Erler et al, 2004;To et al, 2005). These are difficult areas to target due to their very nature-they have limited blood flow and in addition are more resistant to antitumor therapies than better-oxygenated areas.…”

Section: Introductionmentioning

confidence: 99%

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

et al. 2009

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Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo-and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with a-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and therefore prove an effective antitumor therapy. In this report we demonstrate that derivatized a-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular a-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized a-ketoglutarate can permeate multiple layers of cells, reducing HIF1a levels and its target genes in vivo.

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“…In addition, cell survival and cell death are both regulated by hypoxia, in part through the regulation of programmed cell death I and II processes named apoptosis and autophagy respectively. The regulation of apoptosis by hypoxia involves the regulation of the expression of genes such as Bid, Bax, Noxa, Survivin and Mcl-1 [5][6][7][8]. In addition, hypoxia selects cancer cells with reduced apoptotic potential [9].…”

Section: Introductionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

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Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

Cited by 363 publications

References 53 publications

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

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