Regulation of u‐PA gene expression in human prostate cancer
u‐PA contributes to CaP progression, especially in the metastatic androgen‐insensitive state. In vitro, u‐PA is expressed by androgen‐insensitive, but not androgen‐sensitive, CaP cell lines. We hypothesized that in androgen‐sensitive CaP an activated ARE represses u‐PA expression but in androgen‐ins...
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Published in | International journal of cancer Vol. 94; no. 3; pp. 390 - 395 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
New York
John Wiley & Sons, Inc
01.11.2001
Wiley-Liss |
Subjects | |
Online Access | Get full text |
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Summary: | u‐PA contributes to CaP progression, especially in the metastatic androgen‐insensitive state. In vitro, u‐PA is expressed by androgen‐insensitive, but not androgen‐sensitive, CaP cell lines. We hypothesized that in androgen‐sensitive CaP an activated ARE represses u‐PA expression but in androgen‐insensitive CaP this repression is lost and u‐PA is upregulated through MAP kinase signaling pathways. To determine whether binding of the DHT–AR complex to AREs in the u‐PA promoter region represses u‐PA transcription in androgen‐sensitive CaP, we studied 2 PC3 androgen‐insensitive human CaP cell lines stably transfected with AR [PC3(AR)2 and PC3(AR)13] and 1 mock‐transfected cell line [PC3(M)]. In the presence of the synthetic androgen mibolerone, both PC3(AR)2 and PC3(AR)13, but not PC3(M), cells showed decreased u‐PA expression as assayed by Western and Northern blotting. The AR inhibitor flutamide abrogated mibolerone's effect. Androgen regulation of a second gene, PSA, was also demonstrated in the PC3(AR)2 cell line. To explore the pathway stimulating u‐PA expression in CaP, we performed transient transfections in PC3(AR)2 cells using u‐PA promoter‐regulated CAT reporter constructs. Compared to full‐length u‐PA promoter–CAT constructs, either deletion or mutation of the 5′ AP‐1 or PEA3 site reduced CAT expression. The location of androgen responsiveness in the u‐PA promoter was not identified through the combination of promoter search and transient transfection assays, indicating that a more complicated mechanism is involved in the AR‐mediated downmodulation of u‐PA expression. © 2001 Wiley‐Liss, Inc. |
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Bibliography: | Fax: +916‐734‐8094 The views expressed herein represent those of the authors and do not necessarily represent the position of the State of California, Department of Health Services. Mention of trade name, proprietary product or specific equipment does not constitute a guaranty by the Department of Health Services, nor does it imply approval to the exclusion of other products. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0020-7136 1097-0215 |
DOI: | 10.1002/ijc.1469 |