Prostaglandin E2 Induces Hypoxia-inducible Factor-1α Stabilization and Nuclear Localization in a Human Prostate Cancer Cell Line

Liu, Xin Hua; Kirschenbaum, Alexander; Lü, Min; Shen, Yao; Dosoretz, A.M.; Holland, James F.; Levine, Alice C.

doi:10.1074/jbc.m201095200

Cited by 197 publications

(160 citation statements)

References 43 publications

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“…5B, exposure of GFP-HIF1a/EMT6 cells to 10 Amol/L PGE 2 induced nuclear translocation of the GFP-tagged HIF-1a protein. This is in excellent agreement with the findings of Liu et al (17), who showed that PGE 2 exposure resulted in significant nuclear localization of HIF-1a in PC-3ML human prostate cancer cells under normoxic conditions. We find that Photofrin-PDT also strongly induced the translocation of the fusion protein from the cytosol to the nucleus.…”

Section: Discussionsupporting

confidence: 82%

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Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α

Mitra¹,

Cassar²,

Niles

et al. 2006

Molecular Cancer Therapeutics

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Photodynamic therapy (PDT) induces the expression of the hypoxia-inducible factor 1A (HIF-1A) subunit of the HIF-1 transcription factor and its target genes in vitro and in vivo. PDT also induces the expression of the enzyme cyclooxygenase-2 and its metabolite, prostaglandin E 2 (PGE 2 ). PGE 2 and hypoxia act independently and synergistically to increase HIF-1A accumulation and nuclear translocation. To examine the expression of HIF-1 target genes in response to PDT-mediated oxidative stress and PGE 2 under normoxic conditions, we established EMT6 cells transfected with a plasmid consisting of a hypoxia response element promoter and a downstream gene encoding for green fluorescent protein (GFP). To examine the temporal kinetics of HIF-1A nuclear translocation in response to PDT, we transfected a second line of EMT6 cells with a GFP-tagged HIF-1A fusion vector. Cell monolayers were incubated with 1 Mg mL À1 Photofrin for 24 h and irradiated with fluences of 1, 2.5, and 5 J cm À2 . Direct measurement of oxygen concentration during irradiation confirmed that cells remained well oxygenated. Cells were also exposed to 1 and 10 Mmol/L PGE 2 for 3 h. In normoxic conditions, Photofrin, PDT, and PGE 2 treatment activated HIF-1A and induced its nuclear translocation. Maximal Photofrin-PDT -mediated HIF-1A activation was intermediate in magnitude between that induced by PGE 2 and that by the hypoxia mimic cobalt chloride. This work establishes that PDT induces significant activation of the HIF-1A pathway in the absence of hypoxia and supports the interpretation that the induction of HIF-1 target genes by PDT may be mediated, at least in part, by the prostaglandin pathway.

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Section: Discussionsupporting

confidence: 82%

“…The fusion protein vector was a gift from Alice Levine (Mount Sinai Medical School, New York, NY) and was prepared by fusing HIF-1a cDNA to the pEGFP (Clontech; ref. 17). The transfection and clone selection procedures were similar to those followed for the 5HRE-GFP/EMT6 cells.…”

Section: Cell Linesmentioning

confidence: 99%

Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α

Mitra¹,

Cassar²,

Niles

et al. 2006

Molecular Cancer Therapeutics

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“…In vitro studies suggested that the COX-2 gene has a hypoxic responsive element and that hypoxia induces the expression of COX-2 mRNA and its protein in human vascular endothelial cells. Liu et al 54 proposed that inhibitors of the COX enzymes prevent angiogenesis by stabilizing HIF-1␣ accumulation under hypoxic conditions. 54 This proposed mechanism is not supported by our findings, which showed a negative statistical correlation between COX-2 expression and HIF-1␣.…”

Section: Discussionmentioning

confidence: 99%

“…Liu et al 54 proposed that inhibitors of the COX enzymes prevent angiogenesis by stabilizing HIF-1␣ accumulation under hypoxic conditions. 54 This proposed mechanism is not supported by our findings, which showed a negative statistical correlation between COX-2 expression and HIF-1␣. In normoxia, the HIF-1␣ protein is maintained at low and often undetectable levels and is overexpressed under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase‐2 expression in human pituitary tumors

Vidal

Kovács

Bell

et al. 2003

Cancer

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BACKGROUNDCyclooxygenase‐2 (COX‐2) plays a role in progression of colon, breast, pancreas, and lung carcinomas. The authors investigated COX‐2 expression in pituitary tumors.METHODSExpression of COX‐2 was evaluated in 164 surgically removed human pituitary tumors. Correlation of COX‐2 with MIB‐1, a cell proliferation marker, as well as angiogenesis, patient age, gender, tumor type, size, invasiveness, and metastatic potential was investigated.RESULTSCyclooxygenase‐2 immunoreactivity was confined to the cytoplasm of tumor cells, whereas the nuclei were unlabeled. Few normal peritumoral adenohypophysial cells showed slight COX‐2 cytoplasmic immunoreactivity. The staining intensity and the percentage of immunopositive cells were higher in tumors. Most pituitary tumors (96%) were COX‐2–immunopositive. Expression was strong in 60 (44%), moderate in 39 (28%), and weak in 32 (24%). Male gonadotroph adenomas and null cell adenomas showed a high level of COX‐2 expression. Growth hormone‐producing adenomas, prolactin‐producing adenomas, thyrotropic hormone‐producing adenomas, female gonadotroph adenomas, silent adrenocorticotropic hormone‐producing adenomas, and silent subtype 3 adenomas had a low level of COX‐2 expression. Significant correlation was demonstrated with patient age, but not with tumor size, invasiveness, and MIB‐1 labeling indices. Expression was medium to high in 76% of macroadenomas and in only 45% of microadenomas. Strong correlations were noted with angiogenesis markers, such as microvessel density and surface density.CONCLUSIONSCorrelation with angiogenesis suggests that COX‐2 may be involved in the regulation of angiogenesis in pituitary tumors. Phamacologic inhibition of COX‐2 activity might suppress angiogenesis in pituitary tumors and may provide a novel approach for medical therapy. Cancer 2003;97:2814–21. © 2003 American Cancer Society.DOI 10.1002/cncr.11387

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“…TGF-β and HGF regulate COX-2 expression in breast and colon carcinoma cells, respectively, and hypoxia potentiates HGFdependent PGE 2 release in colorectal cancer [16,32]. PGE 2 participates in nuclear translocation of exogenously expressed HIF-1α in prostate carcinoma cells [33]. COX-2 inhibition largely prevents MDA-MB231 bone metastasis by decreasing osteoclast number and increasing apoptosis [16].…”

Section: Involvement Of Cox-2-signaling Pathway In the Hypoxic Responsementioning

confidence: 99%

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Maroni

Matteucci²,

Luzzati³

et al. 2010

Breast Cancer Res Treat

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The aim of the present paper was to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally-activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastaticcell engraftment in the bone. In agreement, HIF-1α expression in bone-marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.Keywords bone microenvironment · bone metastasis · breast cancer · COX-2 · HIF-1 3

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Prostaglandin E2 Induces Hypoxia-inducible Factor-1α Stabilization and Nuclear Localization in a Human Prostate Cancer Cell Line

Cited by 197 publications

References 43 publications

Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α

Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α

Cyclooxygenase‐2 expression in human pituitary tumors

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

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