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Antisense Suppression of the Chloride Intracellular Channel Family Induces Apoptosis, Enhances Tumor Necrosis Factor -Induced Apoptosis, and Inhibits Tumor Growth

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Stuart H. Yuspa, Cell Carcinogenesis and Tumor Promotion, Room 3B25, MSC 4255, 37 Convent Drive, Bethesda, MD 20892-4255. Phone: 301-496-2162; Fax: 301-496-8709; E-mail: yuspas{at}mail.nih.gov.

mtCLIC/CLIC4 is a p53 and tumor necrosis factor (TNF) regulated intracellular chloride channel protein that localizes to cytoplasm and organelles and induces apoptosis when overexpressed in several cell types of mouse and human origin. CLIC4 is elevated during TNF-induced apoptosis in human osteosarcoma cell lines. In contrast, inhibition of NFB results in an increase in TNF-mediated apoptosis with a decrease in CLIC4 protein levels. Cell lines expressing an inducible CLIC4-antisense construct that also reduces the expression of several other chloride intracellular channel (CLIC) family proteins were established in the human osteosarcoma lines SaOS and U2OS cells and a malignant derivative of the mouse squamous papilloma line SP1. Reduction of CLIC family proteins by antisense expression caused apoptosis in these cells. Moreover, CLIC4-antisense induction increased TNF-mediated apoptosis in both the SaOS and U2OS derivative cell lines without altering TNF-induced NFB activity. Reducing CLIC proteins in tumor grafts of SP1 cells expressing a tetracycline-regulated CLIC4-antisense substantially inhibited tumor growth and induced tumor apoptosis. Administration of TNF i.p. modestly enhanced the antitumor effect of CLIC reduction in vivo. These results suggest that CLIC proteins could serve as drug targets for cancer therapy, and reduction of CLIC proteins could enhance the activity of other anticancer drugs.

Key Words: CLIC • TNF • NFB • apoptosis • tumor therapy • chloride channel

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