Iejimalides A and B inhibit lysosomal vacuolar H+-ATPase (V-ATPase) activity and induce S-phase arrest and apoptosis in MCF-7 cells

Peter McHenry, Wei Lin Winnie Wang, Edward Devitt, Nicholas Kluesner, Vincent Jo Davisson, Edward McKee, Dirk Schweitzer, Paul Helquist, Martin Tenniswood

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Iejimalides are novel macrolides that are cytostatic or cytotoxic against a wide range of cancer cells at low nanomolar concentrations. A recent study by our laboratory characterized the expression of genes and proteins that determine the downstream effects of iejimalide B. However, little is known about the cellular target(s) of iejimalide or downstream signaling that lead to cell-cycle arrest and/or apoptosis. Iejimalides have been shown to inhibit the activity of vacuolar H+-ATPase (V-ATPase) in osteoclasts, but how this inhibition may lead to cell-cycle arrest and/or apoptosis in epithelial cells is not known. In this study, MCF-7 breast cancer cells were treated with iejimalide A or B and analyzed for changes in cell-cycle dynamics, apoptosis, lysosomal pH, cytoplasmic pH, mitochondrial membrane potential, and generation of reactive oxygen species. Both iejimalides A and B sequentially neutralize the pH of lysosomes, induce S-phase cell-cycle arrest, and trigger apoptosis in MCF-7 cells. Apoptosis occurs through a mechanism that involves oxidative stress and mitochondrial depolarization but not cytoplasmic acidification. These data confirm that iejimalides inhibit V-ATPase activity in the context of epithelial tumor cells, and that this inhibition may lead to a lysosome-initiated cell death process.

Original languageEnglish (US)
Pages (from-to)634-642
Number of pages9
JournalJournal of Cellular Biochemistry
Volume109
Issue number4
DOIs
StatePublished - Mar 1 2010

Keywords

  • Breast cancer
  • Cell cycle
  • Lysosome
  • Macrolide
  • Mitochondria
  • Reactive oxygen species
  • V-ATPase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    McHenry, P., Wang, W. L. W., Devitt, E., Kluesner, N., Davisson, V. J., McKee, E., Schweitzer, D., Helquist, P., & Tenniswood, M. (2010). Iejimalides A and B inhibit lysosomal vacuolar H+-ATPase (V-ATPase) activity and induce S-phase arrest and apoptosis in MCF-7 cells. Journal of Cellular Biochemistry, 109(4), 634-642. https://doi.org/10.1002/jcb.22438