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- Title
Analog of H2 relaxin exhibits antagonistic properties and impairs prostate tumor growth.
- Authors
Silvertown, Josh D.; Symes, Juliane C.; Neschadim, Anton; Nonaka, Takahiro; Kao, Jessica C. H.; Summerlee, Alastair J. S.; Medin, Jeffrey A.
- Abstract
Hormone antagonists can be effective tools to delineate receptor signaling pathways and their resulting downstream physiological actions. Mutation of the receptor binding domain (RBD) of human H2 relaxin (AH2) impaired its biological function as measured by cAMP signaling. In a competition assay, ΔH2 exhibited antagonistic activity by blocking recombinant H2 relaxin from binding to receptors on THP-1 cells. In a flow cytometry-based binding assay, ΔH2 demonstrated weak binding to 293T cells expressing the LGR7 receptor in the presence of biotinylated H2 relaxin. When human prostate cancer cell lines (PC-3 and LNCaP) were engineered to overexpress eGFP, wildtype (WT) H2, or ΔH2, and subsequently implanted into NOD/SCID mice, tumor xenografts overexpressing ΔH2 displayed smaller volumes compared to H2 and eGFP controls. Plasma osmolality readings and microvessel density and area assessment suggest that ΔH2 modulates physiological parameters in vivo. In a second murine model, intratumoral injections of lentivectors engineered to express ΔH2/eGFP led to suppressed tumor growth compared to controls. This study provides further evidence supporting a role for H2 relaxin in prostate tumor growth. More importantly, we report how mutation of the H2 relaxin RBD confers the hormone derivative with antagonistic properties, offering a novel reagent for relaxin research.
- Subjects
HORMONE antagonists; CHEMICAL inhibitors; RELAXIN; PROSTATE cancer; CANCER cells; TUMOR growth
- Publication
FASEB Journal, 2007, Vol 21, Issue 3, p754
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-6847com