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Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis.
Mol Pharm. 2004 Mar-Apr; 1(2):156-65.MP

Abstract

The effects of the separate and combined application of hypoxia and antisense oligonucleotides (ASO) against hypoxia inducible factor 1alpha (HIF1A) on cancer cells were examined. Experiments were carried out on human ovarian carcinoma cells in four series: (1) control [Normoxia (5% CO2 in air), no treatment], (2) hypoxia (1% O2, 5% CO2, and 94% N2 for 48 h), (3) treatment with ASO targeted to HIF1A (48 h), and (4) combined action of hypoxia and ASO. After treatment, the following processes and factors were monitored: apoptosis, cellular metabolism and viability, expression of genes encoding HIF1A, von Hippel-Lindau tumor suppressor protein (VHL), and genes responsible for cell death induction and antiapoptotic defense (P53, BCL2, BAX, and caspases 9 and 3). Expression of caspase 9 and HIF1A protein was confirmed by Western blotting. Liposomes were used as a delivery system of HIF1A ASO. It was found that hypoxia alone significantly disturbed cellular metabolism, reducing the level of respiration by 50% when compared with control. Hypoxia induced apoptosis by upregulating the P53-, BAX-, and caspase-dependent cell death pathways, while activating cellular antiapoptotic defense by the overexpression of BCL2 protein. Both opposing effects were dependent on the overexpression of hypoxia inducible factor. We conclude that hypoxia induces a bimodal effect, simultaneously promoting cell death and activating cellular resistance. The downregulation of HIF1A promoted cell death induction and prevented activation of cellular defense by hypoxia. This suggests that HIF1A is a potential candidate for anticancer therapeutic targeting.

Authors+Show Affiliations

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15832512

Citation

Wang, Yang, et al. "Bimodal Effect of Hypoxia in Cancer: Role of Hypoxia Inducible Factor in Apoptosis." Molecular Pharmaceutics, vol. 1, no. 2, 2004, pp. 156-65.
Wang Y, Pakunlu RI, Tsao W, et al. Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. Mol Pharm. 2004;1(2):156-65.
Wang, Y., Pakunlu, R. I., Tsao, W., Pozharov, V., & Minko, T. (2004). Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. Molecular Pharmaceutics, 1(2), 156-65.
Wang Y, et al. Bimodal Effect of Hypoxia in Cancer: Role of Hypoxia Inducible Factor in Apoptosis. Mol Pharm. 2004 Mar-Apr;1(2):156-65. PubMed PMID: 15832512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. AU - Wang,Yang, AU - Pakunlu,Refika I, AU - Tsao,William, AU - Pozharov,Vitaly, AU - Minko,Tamara, PY - 2005/4/19/pubmed PY - 2005/7/12/medline PY - 2005/4/19/entrez SP - 156 EP - 65 JF - Molecular pharmaceutics JO - Mol Pharm VL - 1 IS - 2 N2 - The effects of the separate and combined application of hypoxia and antisense oligonucleotides (ASO) against hypoxia inducible factor 1alpha (HIF1A) on cancer cells were examined. Experiments were carried out on human ovarian carcinoma cells in four series: (1) control [Normoxia (5% CO2 in air), no treatment], (2) hypoxia (1% O2, 5% CO2, and 94% N2 for 48 h), (3) treatment with ASO targeted to HIF1A (48 h), and (4) combined action of hypoxia and ASO. After treatment, the following processes and factors were monitored: apoptosis, cellular metabolism and viability, expression of genes encoding HIF1A, von Hippel-Lindau tumor suppressor protein (VHL), and genes responsible for cell death induction and antiapoptotic defense (P53, BCL2, BAX, and caspases 9 and 3). Expression of caspase 9 and HIF1A protein was confirmed by Western blotting. Liposomes were used as a delivery system of HIF1A ASO. It was found that hypoxia alone significantly disturbed cellular metabolism, reducing the level of respiration by 50% when compared with control. Hypoxia induced apoptosis by upregulating the P53-, BAX-, and caspase-dependent cell death pathways, while activating cellular antiapoptotic defense by the overexpression of BCL2 protein. Both opposing effects were dependent on the overexpression of hypoxia inducible factor. We conclude that hypoxia induces a bimodal effect, simultaneously promoting cell death and activating cellular resistance. The downregulation of HIF1A promoted cell death induction and prevented activation of cellular defense by hypoxia. This suggests that HIF1A is a potential candidate for anticancer therapeutic targeting. SN - 1543-8384 UR - https://www.unboundmedicine.com/medline/citation/15832512/Bimodal_effect_of_hypoxia_in_cancer:_role_of_hypoxia_inducible_factor_in_apoptosis_ L2 - https://doi.org/10.1021/mp034031n DB - PRIME DP - Unbound Medicine ER -