Hypoxia-Inducible Factor-1 (HIF-1) Up-Regulates Adrenomedullin Expression in Human Tumor Cell Lines during Oxygen Deprivation: A Possible Promotion Mechanism of Carcinogenesis

Garayoa, Mercedes; Martı́nez, Alfredo; Lee, Sunmin; Pı́o, Rubén; An, Won Gun; Neckers, Len; Trepel, Jane B.; Montuenga, Luis M.; Ryan, Heather E.; Johnson, Randall S.; Gassmann, Max; Cuttitta, Frank

doi:10.1210/mend.14.6.0473

Cited by 195 publications

(144 citation statements)

References 57 publications

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“…Both ADM and bFGF are known to be upregulated by hypoxia (Cormier-Regard et al, 1998;Nakayama et al, 1998;Le and Corry, 1999;Nguyen and Claycomb, 1999;Garayoa et al, 2000). TAM has been shown to induce hypoxia in MCF-7 xenografts (Evans et al, 1997).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre-and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre-but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

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Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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“…1). To examine the effects of Txn1 overexpression on HIF-1α activity, we determined the mRNA levels, in normoxic and hypoxic conditions, of two genes, VEGF and ADM, which are angiogenic growth factors induced by HIF-1α (Cormier-Regard et al, 1998;Forsythe et al, 1996;Garayoa et al, 2000). We found that the hypoxic-induction of VEGF and ADM mRNA was significantly increased in HeLa, HT-29 and EMT6 cells overexpressing Txn1, but not in MCF-7 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of HIF-1α Activity by Overexpression of Thioredoxin is Independent of Thioredoxin Reductase Status

Naranjo‐Suarez

Carlson

Tobe

et al. 2013

Molecules and Cells

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Under hypoxic conditions, cells activate a transcriptional response mainly driven by hypoxia-inducible factors (HIFs). HIF-1α stabilization and activity are known to be regulated by thioredoxin 1 (Txn1), but how the thioredoxin system regulates the hypoxic response is unknown. By examining the effects of Txn1 overexpression on HIF-1α function in HeLa, HT-29, MCF-7 and EMT6 cell lines, we found that this oxidoreductase did not stabilize HIF-1α, yet could increase its activity. These effects were dependent on the redox function of Txn1. However, Txn1 deficiency did not affect HIF-1α hypoxic-stabilization and activity, and overexpression of thioredoxin reductase 1 (TR1), the natural Txn1 reductase, had no influence on HIF-1α activity. Moreover, overexpression of Txn1 in TR1 deficient HeLa and EMT6 cells was still able to increase HIF-1α hypoxic activity. These results indicate that Txn1 is not essential for HIF-1α hypoxic stabilization or activity, that its overexpression can increase HIF-1α hypoxic activity, and that this effect is observed regardless of TR1 status. Thus, regulation of HIF-1α by the thioredoxin system depends on the specific levels of this system's major components.

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“…41 AM has been shown to stimulate tumor angiogenesis through induction of HIF-1. 20 In addition, AM acts as a proangiogenic factor in vivo in breast cancer 42 and endometrial tumors. 43 Therefore, it will be of interest to examine interaction between AM, IL-8 and IL-13R␣2 in relation to tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…18 AM expression and secretion is stimulated by hypoxia, lipopolysaccharide and NO. 17,19,20 In the context of cancer, AM seems to play a growth-modulatory effect in prostate carcinoma. To investigate the role of AM in prostate carcinoma, we previously generated PC-3 cell line clones, which express high levels of AM.…”

mentioning

confidence: 99%

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

Gonzalez-Moreno

Calvo

Joshi

et al. 2004

Intl Journal of Cancer

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Human adrenomedullin (AM) is a 52 amino acid peptide, which shares homology with the calcitonin gene-related peptide. Overexpression of AM in the prostate carcinoma cell line PC-3 results in growth inhibition with a 20% (for human AM) and 35% (for rat AM) increase in doubling time compared to parental or mocktransfected cells. We demonstrate by gene expression profiling that AM overexpression results in the dysregulation of approximately 100 genes. Examples of such genes include many involved in the formation of the cytoskeleton, cell adhesion and the extracellular matrix, as well as regulators of the cell cycle and apoptosis, cytokines and transcription factors. Several genes related to cell growth arrest, such as GADD45, IGF-BP6 and RUNX-3, are upregulated by AM. Interestingly, interleukin-13 receptor ␣2 (IL-13R␣2) transcripts were significantly increased in clones overexpressing AM, which was confirmed by semiquantitative RT-PCR analysis. In addition, PC-3 cells treated with AM showed an overexpression of IL-13R␣2, which was abolished when cells were preincubated with an anti-AM blocking antibody. When PC-3 cells overexpressing AM and the IL-13R␣2 were treated with the highly specific IL13-PE38 cytotoxin, which binds to this receptor, a concentration-dependent inhibition of protein synthesis was observed. The IC 50 (concentration of cytotoxin inhibiting protein synthesis by 50%) ranged from 1 to 4 ng/ml. This cytotoxicity was specific as it was neutralized by the excess of IL-13 and confirmed by clonogenic assays. This study describes a novel AM-induced mechanism of tumor sensitization through the upregulation of functional IL-13R␣2 chain, an ideal target for the highly specific recombinant chimeric cytotoxin IL13-PE38. © 2004 Wiley-Liss, Inc.Key words: cDNA microarrays; prostate cancer; adrenomedullin; IL-13R␣2; gene expression profiling Prostate carcinoma is the second leading cause of cancer mortality among men in the United States. 1 The 5-year relative survival rate for the patients whose tumors are diagnosed with local or regional disease approaches 100%, but the relative 10-and 15-year survival rates are reduced to 75% and 54%, respectively. 1 Although localized prostate cancer may be successfully treated, 70% of patients eventually progress and develop metastasis. The current nonsurgical therapeutic regimens for treating prostate carcinoma include radio-, hormonal-and chemotherapy, as well as a combination of these regimens, depending on specific circumstances of the patient. The limited success of treating particular forms of prostate cancer requires that additional targets for therapy be identified and tested.Expression of adrenomedullin, an amidated peptide that was originally isolated from human pheochromocytoma, 2 has been documented in both the human and rat prostate, 3 human prostate carcinoma 4 and prostate cancer cell lines, 4 where it has been suggested that adrenomedullin (AM) may act as an autocrine/ paracrine factor. Human AM consists of 52 amino acids (50 amino acids for rat AM) and shar...

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Hypoxia-Inducible Factor-1 (HIF-1) Up-Regulates Adrenomedullin Expression in Human Tumor Cell Lines during Oxygen Deprivation: A Possible Promotion Mechanism of Carcinogenesis

Abstract: Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (

Cited by 195 publications

References 57 publications

Tamoxifen induction of angiogenic factor expression in endometrium

Tamoxifen induction of angiogenic factor expression in endometrium

Regulation of HIF-1α Activity by Overexpression of Thioredoxin is Independent of Thioredoxin Reductase Status

Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin

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