The superoxide dismutase inhibitor diethyldithiocarbamate has antagonistic effects on apoptosis by triggering both cytochrome c release and caspase inhibition

Free Radical Biology & Medicine
Anne DumayJean-Luc Vayssière

Abstract

Tumor necrosis factor-alpha (TNF-alpha) and etoposide both trigger a large and rapid production of reactive oxygen species (ROS) in HeLa cells. This occurs before translocations of the proapoptotic Bax and cytochrome c proteins, the loss of mitochondrial membrane potential (DeltaPsim), and apoptosis. We have used diethyldithiocarbamate (DDC), a well-known inhibitor of Cu, Zn superoxide dismutase to study the role of ROS in this system. We report that DDC strongly inhibits caspase activation, loss of DeltaPsim, and cell death induced by TNF-alpha or etoposide. Surprisingly, DDC does not inhibit Bax and cytochrome c translocations. On the contrary, we have observed that DDC can trigger the translocations of these proteins by itself, without altering DeltaPsim. Here, we report that DDC has at least two antagonistic apoptosis regulation functions. First, DDC triggers ROS-dependent Bax and cytochrome c translocations, which are potentially proapoptotic, and second, DDC inhibits caspase activation and activity, loss of DeltaPsim, and cell death, in a ROS-independent manner. Our results suggest an interesting model in which ROS-dependent Bax and cytochrome c translocations can be studied without interference from later apoptotic events.

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Citations

Aug 2, 2008·Reproduction, Fertility, and Development·B D Whitaker, J W Knight
Oct 13, 2011·Journal of Applied Toxicology : JAT·Seref AlpsoyAsuman Gedikbasi
Oct 15, 2011·Journal of Applied Toxicology : JAT·Seref AlpsoyAsuman Gedikbasi
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Jul 20, 2010·Biochemical and Biophysical Research Communications·Nathalie Le FlochJean-Luc Vayssière
Oct 27, 2016·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Prajakta A DhageShobha Y Bhargava
Feb 5, 2021·Parasitology·Sajad RashidiPaul Nguewa
Mar 23, 2021·Oxidative Medicine and Cellular Longevity·Hui-Ru WangHsueh-Wei Chang
May 29, 2021·Scientific Reports·Johny Wysllas de Freitas OliveiraMarcelo Sousa Silva

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