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Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells
Author(s) -
Antalis Toni M.,
Reeder Jennifer A.
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910620521
Subject(s) - urokinase receptor , butyrate , messenger rna , plasminogen activator , gene expression , signal transduction , microbiology and biotechnology , biology , transcription (linguistics) , plasminogen activator inhibitor 1 , regulation of gene expression , cancer research , gene , chemistry , biochemistry , endocrinology , linguistics , philosophy , fermentation
Butyrate is a potent differentiating agent present in high concentrations in colonic lumen as a result of metabolic breakdown of dietaiy fibre and, as such, may directly influence colonic cancer progression. We have investigated the effects of butyrate on an enzyme system important in colonic tumour progression, the plasminogen‐activating system, in a poorly differentiated colon cancer cell. Butyrate was found to induce a rapid and transient increase in plasminogen activator inhibitor type 1 (PA1‐1) mRNA while concomitantly suppressing the constitutive production of both urokinase‐type plasminogen activator (uPA) and uPA receptor (uPAR) mRNA transcripts. We have investigated the mechanisms involved in mediating these effects by run‐on transcription and RNA stability analyses. Our data show that PA1‐1 mRNA induction occurs through both regulation of the stability of the alternately spliced 3.3 kb PA1‐1 mRNA transcript and induction of the 2.4 kb PA1‐1 mRNA transcript. Studies using modulators of signal transduction pathways demonstrate that induction of PA1‐1 mRNA synthesis is independent of protein kinase C but dependent on the activation of protein kinase A. Suppression of uPA mRNA by butyrate was found to occur by down‐regulation of gene transcription through a process independent of de novo protein synthesis. The transcription rate of the uPAR gene was not modulated by butyrate, but rapid turnover of the uPAR gene by butyrate was dependent on ongoing protein synthesis. Our results demonstrate that butyrate can effect rapid changes in the expression of genes of the plasminogen‐activating system through several different mechanisms in a gene‐specific manner. © 1995 Wiley‐Liss, Inc.