J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/07/449/21 $2.00
Volume 138, Number 2, July 28, 1997 449-469

Mitochondrial Proliferation and Paradoxical Membrane Depolarization during Terminal Differentiation and Apoptosis in a Human Colon Carcinoma Cell Line

Mariangela Mancini,^* Benjamin O. Anderson,^* Elizabeth Caldwell,^§ Monireh Sedghinasab,^* Philip B. Paty, and David M. Hockenbery

^* Department of Surgery, University of Washington, Seattle, Washington 98195;  Division of Clinical Research and Molecular Medicine, and ^§ Electron Microscope Laboratory, Shared Resources, Administrative Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98195; and  Department of Surgery, Memorial Sloan Kettering Cancer Center, New York 10021

Herbimycin A, a tyrosine kinase inhibitor, induces cellular differentiation and delayed apoptosis in Colo-205 cells, a poorly differentiated human colon carcinoma cell line. Cell cycle analysis in conjunction with end labeling of DNA fragments revealed that G₂ arrest preceded apoptotic cell death. Ultrastructural examination of herbimycin-treated cells demonstrated morphologic features of epithelial differentiation, including formation of a microvillar apical membrane and lateral desmosome adhesions. A marked accumulation of mitochondria was also observed. Fluorometric analysis using the mitochondrial probes nonyl-acridine orange and JC-1 confirmed a progressive increase in mitochondrial mass. However these cells also demonstrated a progressive decline in unit mitochondrial transmembrane potential (_m) as determined by the _m-sensitive fluorescent probes rhodamine 123 and JC-1 analyzed for red fluorescence. In concert with these mitochondrial changes, Colo-205 cells treated with herbimycin A produced increased levels of reactive oxygen species as evidenced by oxidation of both dichlorodihydrofluorescein diacetate and dihydroethidium. Cell-free assays for apoptosis using rat-liver nuclei and extracts of Colo-205 cells at 24 h showed that apoptotic activity of Colo-205 lysates requires the early action of mitochondria. Morphological and functional mitochondrial changes were observed at early time points, preceding cleavage of poly (ADP-ribose) polymerase.

These results suggest that apoptosis in differentiated Colo-205 cells involves unrestrained mitochondrial proliferation and progressive membrane dysfunction, a novel mechanism in apoptosis.

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