A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells
Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypox...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2005-10-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558605801137 |
| _version_ | 1819030665446817792 |
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| author | Stefania Merighi Annalisa Benini Prisco Mirandola Stefania Gessi Katia Varani Edward Leung Stephen MacLennan Pier Giovanni Baraldi Pier Andrea Borea |
| author_facet | Stefania Merighi Annalisa Benini Prisco Mirandola Stefania Gessi Katia Varani Edward Leung Stephen MacLennan Pier Giovanni Baraldi Pier Andrea Borea |
| author_sort | Stefania Merighi |
| collection | DOAJ |
| description | Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02), adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2) protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells. |
| first_indexed | 2024-12-21T06:33:46Z |
| format | Article |
| id | doaj.art-51ce1d4485294765a905df4c65343ef7 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-21T06:33:46Z |
| publishDate | 2005-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-51ce1d4485294765a905df4c65343ef72022-12-21T19:12:56ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022005-10-0171089490310.1593/neo.05334A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma CellsStefania Merighi0Annalisa Benini1Prisco Mirandola2Stefania Gessi3Katia Varani4Edward Leung5Stephen MacLennan6Pier Giovanni Baraldi7Pier Andrea Borea8Department of Clinical and Experimental Medicine-Pharmacology Unit, University of Ferrara, Ferrara 44100, ItalyDepartment of Clinical and Experimental Medicine-Pharmacology Unit, University of Ferrara, Ferrara 44100, ItalyDepartment of Human Anatomy, Pharmacology, and Forensic Medicine, Institute of Normal Human Anatomy, Ospedale Maggiore, University of Parma, Parma 43100, ItalyDepartment of Clinical and Experimental Medicine-Pharmacology Unit, University of Ferrara, Ferrara 44100, ItalyDepartment of Clinical and Experimental Medicine-Pharmacology Unit, University of Ferrara, Ferrara 44100, ItalyKing Pharmaceuticals R&D, Cary, NC 27513, USAKing Pharmaceuticals R&D, Cary, NC 27513, USADepartment of Pharmaceutical Sciences, University of Ferrara, Ferrara 44100, ItalyCentro Nazionale di Eccellenza per to Sviluppo di Metodologie innovative per to studio ed il trattamento delle patologie infiammatorie, University of Ferrara, Ferrara 44100, ItalyHypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02), adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2) protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.http://www.sciencedirect.com/science/article/pii/S1476558605801137adenosineA3 receptorsHIF-1αhypoxiatumor cells |
| spellingShingle | Stefania Merighi Annalisa Benini Prisco Mirandola Stefania Gessi Katia Varani Edward Leung Stephen MacLennan Pier Giovanni Baraldi Pier Andrea Borea A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells Neoplasia: An International Journal for Oncology Research adenosine A3 receptors HIF-1α hypoxia tumor cells |
| title | A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells |
| title_full | A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells |
| title_fullStr | A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells |
| title_full_unstemmed | A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells |
| title_short | A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells |
| title_sort | a3 adenosine receptors modulate hypoxia inducible factor 1a expression in human a375 melanoma cells |
| topic | adenosine A3 receptors HIF-1α hypoxia tumor cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558605801137 |
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