TIMP‐3 promotes apoptosis in nonadherent small cell lung carcinoma cells lacking functional death receptor pathway

Abstract

Tissue inhibitor of metalloproteinases-3 (TIMP-3) has previously been identified as a tumor suppressor for adherent malignant and normal cells. TIMP-3 inhibits adhesion of cells to extracellular matrix and promotes apoptosis through death receptoractivated, caspase-8-mediated pathway. Here, we have studied the effect of adenovirally mediated overexpression of TIMP-3 on small cell lung cancer (SCLC) cell lines SW2 and N417, which grow in suspension and lack functional caspase-8. The results show that adenoviral delivery of TIMP-3 promotes apoptotic cell death in SCLC cells in the absence of caspase-8 activation. These results suggest TIMP-3 as a promising therapeutic anticancer protein also in nonadherent malignant cells lacking functional death receptor signaling.Proteolytic turnover of basement membrane and extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is an important event in tumor growth, invasion and metastasis.

Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells

“…19 TIMP3 induces apoptosis through both the caspase-dependent and caspase-independent pathways. 20 In our study, Ad-TIMP3 induced apoptotic morphology in cancer cells. Overexpression of TIMP3 induces release of cytochrome-c and activates the caspase-8 and caspase-9 pathways, both resulting in cancer cell apoptosis.…”

“…21 Bond et al 21 reported that TIMP3 induces apoptosis through a Fas-associated death domain-dependent type II apoptotic pathway. On the other hand, Kallio et al 20 showed that TIMP3 is capable of inducing apoptosis in the absence of caspase-8 activation in human small cell lung carcinoma cells, suggesting other pathways besides death receptor signaling. Our previous study also showed that Ad-TIMP3 induced p53 expression in human cancer cell lines Hela and Caski.…”

Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma

“…Unlike other TIMP variants (TIMP-1, 2, and 4), TIMP-3 has poor aqueous solubility and is a component of the ECM (5). Studies have demonstrated that TIMP-3 might function as a potential tumor suppressor gene through induction of tumor cell apoptosis, prevention of tumor ECM remodeling, and inhibition of tumor-derived angiogenic activity (5,6) The expression of TIMP-3 is silenced in various types of malignant carcinoma (7). Regulation of TIMP-3 expression may be influenced by many upstream and downstream transcription factors.…”

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

“…Further evidence is found by the observation that a number of genes of the identified ''Toxicological Classes'' is commonly modulated in both hSKP-HPC and hHEP exposed to APAP. The upregulated genes, BCL2L11, FOS, HMOX1, TIMP3 and AHR are all associated either to cytotoxic responses or induction of apoptosis [72][73][74][75][76][77] and might be useful molecular biomarkers for hepatotoxicity.…”