Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells

Kunz, Manfred; Moeller, Steffen; Koczan, Dirk; Lorenz, Peter; Wenger, Roland H.; Glocker, Michael O.; Thiesen, Hans‐Juergen; Gross, Gerd; Ibrahim, Saleh M.

doi:10.1074/jbc.m301373200

Cited by 95 publications

(83 citation statements)

References 56 publications

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“…Using a microarray-based approach, we identified angiogenin (ANG) 51 and the cysteine-rich angiogenic inducer 61 (CYR61) 52 as determinants of cellular response to ARSs, both of which are potent mediators of new vessel formation. Furthermore, various metalloproteinases (MMP9, MMP11 and BMP1) and collagens (COL1A2, COL4A2 and COL18A1) also correlated with the cellular response to ARSs.…”

Section: Discussionmentioning

confidence: 99%

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

et al. 2006

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Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by realtime RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesisrelated genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects.

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Section: Discussionmentioning

confidence: 99%

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

et al. 2006

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“…Although HIF controls the expression of many hypoxiaregulated genes, expression profiling studies conducted under hypoxia (21)(22)(23)(24)(25)(26)(27)(28) reveal that HIF activation alone cannot account for the full repertoire of changes that occur intracellularly as oxygen becomes limiting. Hypoxic cells elicit additional HIF-1-independent adaptive responses that contribute to increased survival under low oxygen conditions.…”

Section: Introductionmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Feldman

Chauhan

Koong

2005

Molecular Cancer Research

278

222

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Hypoxia is a physiologically important endoplasmic reticulum (ER) stress that is present in all solid tumors. Numerous clinical studies have shown that tumor hypoxia predicts for decreased local control, increased distant metastases, and decreased overall survival in a variety of human tumors. Hypoxia selects for tumors with an increased malignant phenotype and increases the metastatic potential of tumor cells. Tumor cells respond to hypoxia and ER stress through the activation of the unfolded protein response (UPR). The UPR is an adaptive response to increase cell survival during ER stress. XBP-1 is a critical transcriptional regulator of this process and is required for tumor growth. Pancreatic ER kinase (PKR-like ER kinase) regulates the translational branch of the UPR and is also important in the growth of tumors. Although the exact mechanism has yet to be elucidated, recent data suggest that the UPR affects tumor growth through protection from apoptosis and may influence angiogenic signaling pathways. Targeting various components of the UPR is a promising therapeutic strategy. Understanding the relationship between hypoxia, the UPR, and tumor growth is crucial to improving current cancer therapies. (Mol Cancer Res 2005;3(11):597 -605)

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“…The secretion of angiogenesis factors such as the fibroblast growth factor, VEGF, platelet-derived growth factor, interleukin-8, angiogenin, and CCN1, is enhanced in response to hypoxia (10,(14)(15)(16)(17)(18)(19)(20)(21)(22). The immediate early gene CCN1 (CYR61), a member of the CCN family, codes for a secreted heparin binding protein associated with the cell surface and extracellular matrix (23).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of the human CCN1 promoter was found to be regulated by CREB and activator protein 1 (AP-1) in sphingosine-stimulated smooth muscle cells (31) and by HIF and AP-1 following hypoxia in melanoma cells (21,22). The mouse CCN1 promoter was found to be activated by serum components via a serum response element at position À2 kb and an Egr binding site at position À48 bp (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Meyuhas¹,

Pikarsky²,

Tavor³

et al. 2008

Molecular Cancer Research

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Hypoxia is a prominent feature of solid tumors known to contribute to malignant progression and therapeutic resistance. Cancer cells adapt to hypoxia using various pathways, allowing tumors to thrive in a low oxygen state. Induction of new blood vessel formation via the secretion of proangiogenic factors is one of the main adaptive responses engaged by tumor cells under hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a pivotal role in mediating such responses. In addition, several other transcription factors have also been implicated in hypoxic gene regulation, either independently or in cooperation with HIF-1. In this work, we show that the expression of the angiogenesis-related, immediate early gene CCN1 (formerly known as CYR61), considered to be involved in tumor growth and invasiveness, is enhanced upon hypoxia stress primarily in a protein kinase A and cyclic AMP-responsive element binding protein (CREB) and CRE -dependent manner in various cell lines. The hypoxia-mediated activation of the CCN1 promoter is independent of HIF-1 and HIF-2, as shown by small interfering RNA knockdown. We identify the cis element in the mouse CCN1 promoter responsible for CREB binding to be one of two partial CRE sites present in the promoter. Moreover, we report for the first time that CREB-mediated CCN1 transcription is enhanced in hypoxic regions of tumors in vivo. Identifying and characterizing the molecular mechanisms that govern the response of tumors to hypoxia may be instrumental to identify the tumors that will respond favorably to inhibition of angiogenesis and thus lead to the development of treatments that could complement hypoxia-inducing treatment modalities.

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Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells

Abstract: Hypoxia has a profound influence on progression and metastasis of malignant tumors. In the present report, we used the oligonucleotide microarray technique to identify new hypoxia-inducible genes in malignant melanoma with a special emphasis on angiogenesis factors.

Cited by 95 publications

References 56 publications

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

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