Regulation and interplay of apoptotic and non-apoptotic cell death.
Various death triggers including DNA damage, oxidative stress, and growth factor deprivation promote the loss of mitochondrial membrane potential, leading to the production of reactive oxidative species (ROS) or enhanced permeability of the mitochondrial membrane, otherwise known as mitochondrial membrane permeabilization, by insertion of Bax/Bak into the outer membrane where it interacts with voltage-dependent anion channel (VDAC)/adenine nucleotide transporter (ANT). MMP leads to the release of small pro-apoptotic molecules, which induce caspase-dependent and -independent apoptotic cell death. The production of ROS due to the loss of mitochondrial membrane potential enhances the permeability of lysosomal membranes, resulting in the release of lysosomal proteases, which contribute to mitochondrial membrane permeabilization and the lysosomal degradation mechanism of autophagic cell death. Although defects in apoptotic and non-apoptotic cell death pathways can be carcinogenic, these pathways are more or less preserved within cancer cells and can therefore influence cell death and mediate resistance to cancer treatment. This paper discusses recent advances in determining the molecular mechanisms behind regulation of apoptotic and non-apoptotic cell death, as well as the interplay between these two processes, which may lead to the development of new strategies by which to enhance the therapeutic effects of chemotherapeutic agents.
Kim
R
R
International Radiation Information Centre, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. rkim@hiroshima-u.ac.jp
Emi
M
M
Tanabe
K
K
Murakami
S
S
Uchida
Y
Y
Arihiro
K
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002463:Cell Membrane Permeability; D002477:Cells / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D020169:Caspases