Published online before print April 1, 2004

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(Journal of Leukocyte Biology. 2004;76:169-175.)
© 2004 by Society for Leukocyte Biology

Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions

Saeid Ghavami^*,1, Claus Kerkhoff, Marek Los^,2, Mohammad Hashemi^*,1, Clemens Sorg and Fatemeh Karami-Tehrani^*,3

^* Cancer Research Laboratory, Clinical Biochemistry Department, School of Medical Science, Tarbiat Modarres University, Tehran, Iran; and
Institute of Experimental Dermatology, Münster, Germany

³Correspondence: Clinical Biochemistry Department, Faculty of Medical Sciences, Tarbiat Modaress University, P.O. Box 14115-111, Tehran, I.R., Iran. E-mail: karamitf{at}modares.ac.ir

The protein complex S100A8/A9, abundant in the cytosol of neutrophils, is secreted from the cells upon cellular activation and induces apoptosis in tumor cell lines and normal fibroblasts in a zinc-reversible manner. In the present study, we present evidence that the S100A8/A9 also exerts its apoptotic effect by a zinc-independent mechanism. Treatment of the colon carcinoma cells with different concentrations of human S100A8/A9 or the metal ion chelator diethylenetriaminepentacetic acid (DTPA) resulted in a significant increase of cell death. Annexin V/phosphatidylinositol and Hoechst 33258 staining revealed that cell death was mainly of the apoptotic type. A significant increase in the activity of caspase-3 and -9 was observed in both cell lines after treatment. Caspase-8 activation was negligible in both cell lines. The cytotoxicity/apoptotic effect of human S100A8/A9 and DTPA was inhibited significantly (P<0.05) by Zn⁺² and Cu⁺², more effectively than by Ca²⁺ and Mg²⁺. The antioxidant N-acetyl-L-cysteine inhibited the cytotoxicity/apoptotic effect of S100A8/A9 and DTPA. However, as a result of the different time-courses of both agents and that the S100A8/A9-induced apoptosis was not completely reversed, we conclude that S100A8/A9 exerts its apoptotic effect on two colon carcinoma cell lines through a dual mechanism: one via zinc exclusion from the target cells and the other through a yet-undefined mechanism, probably relaying on the cell-surface receptor(s).

Key Words: caspase activation • polymorphonuclear neutrophils • cytotoxic peptides • calcium-binding protein • zinc-binding protein

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