Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death

Cell Death Differ. 2005 Oct;12(10):1297-309. doi: 10.1038/sj.cdd.4401651.

Abstract

A chemotherapeutic vitamin D analogue, EB1089, kills tumor cells via a caspase-independent pathway that results in chromatin condensation and DNA fragmentation. Employing transmission- and immunoelectronmicroscopy as well as detection of autophagosome-associated LC3-beta protein in the vacuolar structures, we show here that EB1089 also induces massive autophagy in MCF-7 cells. Interestingly, inhibition of autophagy effectively hindered apoptosis-like nuclear changes and cell death in response to EB1089. Furthermore, restoration of normal levels of beclin 1, an autophagy-inducing tumor suppressor gene that is monoallelically deleted in MCF-7 cells, greatly enhanced the EB1089-induced nuclear changes and cell death. Thus, EB1089 triggers nuclear apoptosis via a pathway involving Beclin 1-dependent autophagy. Surprisingly, tumor cells depleted for Beclin 1 failed to proliferate suggesting that even though the monoallelic depletion of beclin 1 in human cancer cells suppresses EB1089-induced autophagic death, one intact beclin 1 allele is essential for tumor cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins
  • Autophagy / drug effects
  • Beclin-1
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cadaverine / analogs & derivatives
  • Cadaverine / pharmacokinetics
  • Calcitriol / analogs & derivatives*
  • Calcitriol / antagonists & inhibitors
  • Calcitriol / pharmacology
  • Cathepsins / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Cryoelectron Microscopy
  • Drug Interactions
  • Genes, Tumor Suppressor
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Membrane Proteins
  • Proteins / genetics
  • Proteins / metabolism
  • Proteins / physiology*
  • RNA, Small Interfering / genetics
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Proteins
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • 3-methyladenine
  • Cathepsins
  • Calcitriol
  • monodansylcadaverine
  • Adenine
  • Cadaverine
  • seocalcitol