The Tumor Suppressor Activity and Signaling Pathways of Mda-7/IL-24 in Hepatic Cancer Cells

Kumiko Kato, Tomoyuki Saeki and Youji Yamazaki

Department of Surgery, The Jikei University School of Medicine

Purpose: Mda-7/IL-24 is a unique cytokine gene belonging to the IL-10 family. Adenoviral-mediated gene transfer of mda-7/IL-24 induces growth suppression and apoptosis selectively in a wide range of cancer cell lines without causing cytotoxity to normal cells. We studied the anti tumor effect and signaling pathways of mda-7/IL-24 in human hepatic cancer cell lines in vitro. Materials and Methods: Overexpression of MDA-7 by a replication-incompetent adenovirus (Ad-mda-7) in human hepatic cancer cell lines, i.e., HepG2 (p53-wild type) and Hep3B (p53-deleted type), was evaluated by immunochemistry and Western blot analysis. Cell proliferation was assayed by a dye exclusion test. Apoptosis signaling proteins (PARP, CASPASE, and BAX) and the JAK/STAT pathway were evaluated by Western blot analysis. Results: Ad-mda-7 inhibited growth in both cell lines 72 hours after transduction (p<0.05). MDA-7 and cleaved PARP expressions were up-regulated after 72 hours in both cell lines. Up-regulation of BAX expression was observed in HepG2 cells, while no difference was observed in Hep3B cells. Cleaved CASPASE-8 expression was detected in both cell lines, and p-STAT3 expressed in HepG2 cells. Conclusions: Mda-7/IL-24 effectively induced apoptosis in hepatic cell lines. The anti tumor effect was proved to occur in p53 and Bax independently and through the activation of caspase cascade pathways. Activation of STAT3 could be involved in the apoptosis pathway.

Key words
apoptosis, mda-7, IL-24, hepatic cancer cell, gene therapy

Reprint requests
Kumiko Kato Department of Surgery, The Jikei University of Medicine
3-25-8 Nishi-shinbashi, Minato-ku, 105-8461 JAPAN

Accepted
February 23, 2005

To read the PDF file you will need Abobe Reader installed on your computer.