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The Journal of cell biology
Jul 28, 1997;138 (2): 449-69.

Mitochondrial proliferation and paradoxical membrane depolarization during terminal differentiation and apoptosis in a human colon carcinoma cell line.

M Mancini, B O Anderson, E Caldwell, M Sedghinasab, P B Paty, D M Hockenbery
Author Information
  1. M Mancini: Department of Surgery, University of Washington, Seattle, Washington 98195, USA.
PMID: 9230085 DOI: 10.1083/jcb.138.2.449

Abstract

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 (DeltaPsim) as determined by the DeltaPsim-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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MeSH Term

Adenocarcinoma
Animals
Apoptosis
Benzoquinones
Cell Cycle
Cell Differentiation
Cell Division
Cell Survival
Cell-Free System
Colon
Colonic Neoplasms
Enzyme Inhibitors
Fluorescent Dyes
Humans
Intracellular Membranes
Lactams, Macrocyclic
Liver
Membrane Potentials
Mitochondria
Oxidation-Reduction
Poly(ADP-ribose) Polymerases
Protein-Tyrosine Kinases
Quinones
Rats
Reactive Oxygen Species
Rifabutin
Tumor Cells, Cultured

Chemicals

Benzoquinones
Enzyme Inhibitors
Fluorescent Dyes
Lactams, Macrocyclic
Quinones
Reactive Oxygen Species
Rifabutin
herbimycin
Poly(ADP-ribose) Polymerases
Protein-Tyrosine Kinases
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 4

Word Cloud

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