Abstract
Abstract Tissue inhibitors of matrix metalloproteinases have multifunctional properties, orchestrating diverse biological activities. Previous studies revealed a novel function of TIMP-1 as an inhibitor of apoptosis in mammalian cells. However, the mechanisms by which TIMP-1 exerts its anti-apoptotic effect are not completely understood. The antiapoptotic effect has been correlated with higher levels of Bcl-Xl. Our earlier studies in a CNS model of metastasis, using HB-1, a TIMP-1 overexpressing lung adenocarcinoma cell line (H2009), resulted in more aggressive tumor kinetics and increased vasculature. The present study was undertaken to elucidate the role of TIMP-1 in apoptosis in our model. Utilizing an apoptosis -specific gene array, we found that TIMP-1 overexpression results in 3-fold increased expression of Bcl-2. H2009 and the TIMP1 over-expressing clone - HB1 were treated with staurosporine to induce apoptosis, followed by analysis for poly ADP-ribose polymerase (PARP) cleavage. HB1 showed marked reduction in PARP cleavage in comparison to the controls. Treatment of HB1 cells with ABT737, an inhibitor of Bcl-2, restored apoptosis resulting in PARP cleavage in this clone. To further confirm this mechanism, we induced transient inhibition of Bcl-2 with siRNA, which also restored PARP cleavage in the HB-1 clone. Thus both chemical and biological inhibition resulted in increased apoptosis. Additionally, immunoprecipitation of Bcl-2 from cell lysate co-immunoprecipitated TIMP-1 suggesting a direct interaction between TIMP-1 and Bcl-2. These investigations identify a relationship between TIMP-1 and Bcl-2 in apoptosis inhibition, contributing to aggressive tumor kinetics, utilizing non-MMP dependent mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4955. doi:1538-7445.AM2012-4955
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