REGULAR ARTICLES

Cell Research(2004) ; 14(2) : 117-124

LIGHT sensitizes IFN¦Ã -ediated apoptosis of HT-29 human carcinoma cells through both death receptor and mitochondria pathways

Man Chao ZHANG*, Hong Peng LIU, Lisa L DEMCHIK , Yi Fan ZHAI, Da Jun YANG

Division of Hematology/Oncology, Department of Internal Medicine, the University of Michigan, Ann Arbor, MI 48109-0934, USA.

Received, Feb 9, 2004  Revised, Mar 4, 2004  Accepted, Mar 10, 2004

Correspondence: Man Chao ZHANG 3111 CCGC, 1500 E. Medical Center Dr. Ann Arbor, MI 48109-0934, USA. 734-647-7949(phone) 734-647-9647 (fax) manchaoz@umich.edu

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Abstract

LIGHT [homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM/TR2)] is a new member of TNF superfamily. The HT-29 colon cancer cell line is the most sensitive to LIGHT-induced, IFNg-mediated apoptosis among the cell lines we have examined so far. Besides downregulation of Bcl-XL, upregulation of Bak, and activation of both PARP [poly (ADP-ribose) polymerase] and DFF45 (DNA fragmentation factor), LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells involves extensive caspase activation. Caspase-8 and caspase-9 activation, as shown by their cleavages appeared as early as 24 h after treatment, whereas caspase-3 and caspase-7 activation, as shown by their cleavages occurred after 72 h of LIGHT treatment. Caspase-3 inhibitor Z-DEVD-FMK (benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone) and a broad range caspase inhibitor Z-VAD-FMK (benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone) were able to block LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells. The activity of caspase-3, which is one of the major executioner caspases, was found to be inhibited by both Z-DEVD-MFK and Z-VAD-FMK. These results suggest that LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells is caspase-dependent, and LIGHT signaling is mediated through both death receptor and mitochondria pathways.

Key words: HT-29, LIGHT, apoptosis, Bcl-XL, caspase.