The hypoxia-inducible factor-1α is a negative factor for tumor therapy

Unruh, Annika; Ressel, Anke; Mohamed, Hamid G; Johnson, Randall S.; Nadrowitz, Roger; Richter, Eckart; Katschinski, Dörthe M.; Wenger, Roland H.

doi:10.1038/sj.onc.1206385

Cited by 317 publications

(279 citation statements)

References 42 publications

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“…However, the roles HIF-1a plays in hypoxiarelated drug resistance are still inconclusive. 6,10,[30][31][32][33] Moreover, how HIF-1 cooperates with p53 to determine drug sensitivity remains poorly known. 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.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Although HIF-1a level is good indicator of poor outcome in clinical data, evidence of the role of HIF-1a in hypoxia-related radiation and drug resistance is inconsistent because of different oxygen concentration and cell lines used in experiments. [5][6][7][8][9][10] HIF-1 knockdownmediated radiation or drug sensitization under normoxia produced negative results in some studies since HIF-1 was expected to play minor roles in the presence of O 2 . Cells with normal or suppressed HIF-1 status were not indicated as the major part of therapy barrier under normoxia.…”

Section: Introductionmentioning

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: 99%

Section: Introductionmentioning

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 loss of ability to express NDRG1 would assist cells to dedifferentiate to a more aggressive phenotype with more metastatic potential. Recently, it has been suggested that hypoxia can induce dedifferentiation and genetic instability of tumour cells, which may account for the heterogeneity and aggressiveness of solid tumours (Reynolds et al, 1996;Jogi et al, 2002;Helczynska et al, 2003;Unruh et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

et al. 2006

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N-myc downstream-regulated gene-1 (NDRG1) is a recently described hypoxia-inducible protein that is upregulated in various human cancers. Pancreatic ductal adenocarcinoma, called pancreatic cancer, is a highly aggressive cancer that is characterised by its avascular structure, which results in a severe hypoxic environment. In this study, we investigated whether NDRG1 is upregulated in these tumours, thus providing a novel marker for malignant cells in the pancreas. By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative. In addition, hyperplastic islets and ducts of nonquiescent pancreatic tissue were positive. To further explore its selective expression in tumours, two well-established pancreatic cancer cell lines of unequal differentiation status were exposed to 2% oxygen. NDRG1 mRNA and protein were upregulated by hypoxia in the moderately differentiated Capan-1 cells; however, its levels remained unchanged in the poorly differentiated Panc-1 cell line. Taken together, our data suggest that NDRG1 will not serve as a reliable marker of tumour cells in the pancreas, but may serve as a marker of differentiation. Furthermore, we present the novel finding that cellular differentiation may be an important factor that determines the hypoxia-induced regulation of NDRG1.

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“…In tumor tissue, the HIF-1-induced gene expression influences tumor growth and impairs tumor response to chemotherapy and radiotherapy. 10,11 Compared to HIF-1, the role of PHDs in tumor formation and progression remains incompletely understood. For PHD2, tumor promoting as well as tumor inhibiting effects are reported.…”

mentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

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The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein stability of the a-subunit of the hypoxiainducible factor-1 (HIF-1), which mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating HIF-1a hydroxylation and thus stability in normoxia. In human cancers, HIF-1a is overexpressed as a result of intratumoral hypoxia which in turn promotes tumor progression. The role of PHD2 for tumor progression is in contrast far from being thoroughly understood. Therefore, we established PHD2 knockdown clones of MDA-MB-231 breast cancer cells and analyzed their tumorforming potential in a SCID mouse model. Tumor progression was significantly impaired in the PHD2 knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing PHD2 expression. In a RNA profile screen, we identified the secreted phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was additionally verified in 294 invasive breast cancer biopsies. In subsequent analyses, we identified that PHD2 alters the processing of transforming growth factor (TGF)-b1, which is highly involved in SPP1 expression. The altered processing capacity was associated with a dislocation of the pro-protein convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might affect tumor-relevant TGF-b1 target gene expression by altering the TGF-b1 processing capacity.

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The hypoxia-inducible factor-1α is a negative factor for tumor therapy

Cited by 317 publications

References 42 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

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

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