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Tumor Necrosis Factor Induces Apoptosis in Mammary Adenocarcinoma Cells by an Increase in Intranuclear Free Ca²⁺ Concentration and DNA Fragmentation¹

Dipartimento di Medicina Interna e Terapia Medica, Clinica Medica I, University of Pavia, I-27100 Pavia, Italy [G. B., M. P., F. T., F. M., G. F.] and Department of Toxicology, Karolinska Institutet, Box 60400, S-104 01 Stockholm, Sweden [P. N., S. O.]

The incubation of human mammary adenocarcinoma cells (BT-20) with tumor necrosis factor in the absence or presence of cycloheximide resulted in progressive DNA fragmentation. This was preceded by a sustained increase in intracellular free Ca²⁺ concentration and was not detected in cells pretreated with intracellular Ca²⁺ chelators, calmodulin antagonists, or activators of protein kinase C. Image analysis of fura-2-loaded BT-20 cells treated with tumor necrosis factor revealed that, in many cells, the initial increase in Ca²⁺ level occurred in a cellular region that corresponded to the localization of the nucleus. Our findings suggest that tumor necrosis factor can promote an increase in intranuclear free Ca²⁺ which, in turn, may stimulate Ca²⁺-dependent endonuclease activity, resulting in DNA fragmentation and apoptosis.

¹ This study was supported by grants from Consiglio Nazionale delle Ricerche (Special Project: Biology and Pathology of Calcium), the Swedish Medical Research Council (Project 03X-2471), and the CFN (Project L-90-08).

² To whom requests for reprints should be addressed, at Department of Toxicology, Karolinska Institutet, Box 60 400, S-104 01 Stockholm, Sweden.

Received 1/17/91. Accepted 12/ 9/91.

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