The IGF-Rl axis appears to play a major role in regulating matrix metalloproteinase-2 production and the tumorigenesis of prostate cancer. Our preliminary data indicate that IL- 10 blocks IGF- 1 induced MMP-2 synthesis in primary human prostate tumor lines (i.e. HPCA-10c cells immortalized with the telomerase gene). We have discovered that IL- 10 triggers signaling by a novel 'LIM domain' signal protein (33 Kda) which binds a silencer element (upstream of a p53 enhancer site) of the MM-P-2 promoter to block IGF-1 (and p53) induced transcription. Two hypotheses will be tested in this grant application, namely that: (1) the IL-10:IL-l0 receptor axis down regulates MMP-2 production (via activation of a novel 33 Kda (S if) transcription regulatory protein that binds a suppressor element (Si) of the MMP-2- 5' promoter; and that (2) IL-10 transfection blocks IGF-i :IGF-receptor 1 axis induction of MMP-2 expression in vitro. The IL-10 experiments will determine the influence of IL-10 transfection on the IGF-1R axis and MMP-2 expression in two primary human prostate cancer cell lines (i.e. androgen dependent HPCA-10a cells and androgen independent HPCA- 1 Oc lines) immortalized by transfection with the telomerase gene. The behavior of HPCA-i0a and lOc cells (i.e. IL-lO transfected cells) will be compared in an orthotopic tumor model in SCID mice in terms of growth, angiogenesis and metastatic behavior; plus mouse survival rates. Gene expression profiles related to the IGF-R1 and IL-10R axis (i.e. Sif and MMP-2) will be assessed by Northern blotting and immunological techniques. Finally, the expression of these genes (and related genes) will be examined in archival (-150/yr) human prostate glands (i.e. benign, HGPIN, cancer) seminal vesicle and localized metastases by immunolabeling of whole mount sections. Overall, the studies should determine whether the IL-i OR and/or IGF-R1 axis play a role in prostate tumor growth and metastasis. Development of therapeutic agents, which target the IL-10R or IGF-R1 axis should be beneficial in the treatment of the disease.
| Wang, Min; Hu, Youji; Shima, Ischiro et al. (2002) IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines. Cancer Biol Ther 1:556-63 |
