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IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines
Journal article   Open access   Peer reviewed

IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines

Min Wang, Youji Hu, Ischiro Shima and Mark E Stearns
Cancer biology & therapy, v 1(5), pp 556-563
Sep 2002
DOI: https://doi.org/10.4161/cbt.1.5.222
PMID: 12496489
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.4161/cbt.1.5.222View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Antineoplastic Agents - pharmacology Cell Line Cell Transplantation Enhancer Elements, Genetic Enzyme Activation Gene Expression Regulation, Neoplastic Genistein - pharmacology Humans Interleukin-10 - antagonists & inhibitors Interleukin-10 - metabolism Male Mice Mice, SCID Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Receptors, Interleukin - metabolism Receptors, Interleukin-10 Signal Transduction Tissue Inhibitor of Metalloproteinase-1 - metabolism Transplantation, Heterologous Type C Phospholipases - pharmacology
An IL-10 responsive signal protein, termed IL-10E1, was cloned from human prostate cancer PC-3 ML cells based on its binding affinity for a novel enhancer element (i.e., HTE-1: 5'-CACGATGACTCATCACTGTTGAAAGACA-3') of the Tissue Inhibitor of metalloproteinase-1 (TIMP-1) gene. Electrophoretic mobility shift assays (EMSAs) and enzyme linked immuno-sandwich assays (ELISAs) showed that IL-10 stimulated the rapid translocation of IL-10E1 to the nucleus and the activation of TIMP-1 expression in 4 different androgen dependent primary prostate tumor lines generated in our laboratory (i.e. HPCA-5a, 5b, 5c and 5d lines). IL-10 signaling was blocked by a variety of agents, including IL-10 receptor antibodies, alpha-toxin, and Genistein. The inhibition of IL-10 signaling and IL-10E1 expression correlated directly with a significant decrease in TIMP-1 expression by the HPCA-5a, 5b, 5c and 5d cell lines. Following permanent transfection of HPCA-5a and 5c cells with the IL-10 gene the growth of tumor xenografts in SCID CB17 mice was severely retarded, yielding tiny, poorly vascularized tumors by approximately 90 days post-inoculation s.c. ELISAs showed that these tumors expressed elevated levels of IL-10, IL-10E1 and TIMP-1 compared with tumors from non-transfected or Mock transfected cell lines. We conclude that the IL-10/IL-10 receptor axis (and IL-10E1 signaling) regulation of TIMP-1 expression plays a key role in inhibiting tumor growth, perhaps by blocking tumor vascularization.

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Web of Science research areas
Oncology
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