The intrinsic mitochondrial membrane potential (δψm) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis

Barbara G. Heerdt, Michele A. Houston, Andrew J. Wilson, Leonard H. Augenlicht

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Transformation of colonic epithelial cells is characterized by decreased mitochondrial activity, increased mitochondrial membrane potential (Δψm), and disruptions in the equilibrium between cell proliferation and death by apoptosis. We have previously shown that an intact Δψm is essential for growth arrest and apoptosis induced by butyrate, a physiological regulator of maturation in these cells, suggesting a role for the Δψm in the initiation and integration of proliferation and apoptotic pathways. To extend this work, we have generated isogenic cell lines, from SW620 human colonic carcinoma cells, which exhibit significant differences in intrinsic Δψm. These differences in Δψm are not linked to alterations in viability, Bcl-2 levels, or the differentiation status of the cells. However, compared with parental cells and those with increased Δψm, cells with decreased intrinsic Δψm exhibit significantly higher levels of steady-state mitochondrial mRNA and butyrate-induced p21 WAF1/Cip1 and G0-G1 arrest. Moreover, despite butyrate-mediated translocation of proapoptotic Bax and Bak to the mitochondria, fewer cells with elevated intrinsic Δψm exhibit concomitant cytochrome c release, and cells with elevated Δψ m undergo significantly lower levels of Δψm. dissipation and apoptosis than parental cells, or cells with decreased Δψm. Homeostasis of the colonic mucosa depends on balancing cell proliferation with apoptosis, and mitochondrial abnormalities are associated with disruptions in this balance. Thus, by affecting steady-state mitochondrial activity and the extent to which cells enter growth arrest and apoptotic cascades, these data establish a role for the intrinsic Δψm in contributing to the probability of colonic tumorigenesis and progression.

Original languageEnglish (US)
Pages (from-to)6311-6319
Number of pages9
JournalCancer Research
Volume63
Issue number19
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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