Prostatic carcinoma is the most frequently diagnosed cancer in men in the United States, however, its etiology is largely unknown. The mechanisms of invasion and metastases of prostate carcinoma are currently topics of intense study. Our research focused on IL-1β induced expression of the matrix metalloproteinase, matrilysin, in the prostate. Matrilysin is suspected to be involved with invasive and/or metastatic properties of prostate carcinoma cells and has been shown to be up regulated in prostate cancer. Inhibition of NFκB completely abrogated IL-1β induced promatrilysin expression, however, inhibition of protein synthesis with cyclohexamide completely blocked induction of IL-1β stimulated matrilysin mRNA which indicated that synthesis of one or more signaling factors was required for potentiation of promatrilysin expression by IL-1β. IL-1β also induced expression of IL-6 by LNCaP cells; and, recombinant IL-6 stimulated promatrilysin expression. Cyclohexamide did not inhibit induction of promatrilysin by IL-6 indicating that IL-6 induced promatrilysin expression was direct and did not require new protein synthesis. In addition, our data revealed that inhibition of IL-6 activity with a neutralizing antibody directed against the IL-6 ligand, blocked IL-1β induced promatrilysin expression. Further investigation of this pathway suggested that STAT3 acts downstream to regulate IL-6 induced matrilysin expression. Dominant negative STAT3 inhibited both IL-1β and IL-6 induced activity of a co-transfected matrilysin-luciferase reporter construct. Because of their relevance to prostate cancer, we next examined the effect of androgens on IL-1β induced promatrilysin expression. We found that the androgens, testosterone and dihydrotestosterone blocked IL-1β induced promatrilysin and IL-6 expression through inhibition of NFκB. Androgens showed no effect on IL-6 induced promatrilysin expression indicating that STAT3 is not regulated by androgens in our system. Therefore, our data indicate that IL-1β induced promatrilysin expression is regulated by NFκB mediated synthesis of IL-6 and STAT3 signaling; and, through inhibition of NFκB, androgens can block IL-1β induced promatrilysin. Degradation of the extracellular matrix by MMPs is thought to play a role in prostate cancer invasion and metastatasis. These data provide evidence that IL-1β and IL-6 mediated expression of matrilysin may be involved in prostate cancer progression.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/279914 |
| Date | January 2001 |
| Creators | Stratton, Mimi Suzanne |
| Contributors | Bowden, G. Timothy |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
Page generated in 0.0017 seconds