Rainey 2019 MiP2019

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Nathan Rainey
Mitochondria are not the primary target of curcumin-induced autophagy and apoptosis.

Link: MiP2019

Rainey NE, Petit PX (2019)

Event: MiP2019

COST Action MitoEAGLE

Curcumin, a major active component of turmeric (Curcuma longa, L.), has inhibitory effects on cancers. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effects of curcumin is unclear as well as the role of mitochondria in such processes. Unfortunately, in our observations, curcumin do not localize at the mitochondrial compartment.

Since, there is an important consensus showing that ER stress may play a role in the cytotoxicity of many natural compounds, we investigated mechanistic aspects of the destabilization of the endoplasmic reticulum but also the status of the lysosomal compartment involved in mitochondrially associated apoptosis by combined image and flow cytometry. Curcumin located in ER induces a stress causing an UPR response and calcium release which in turn destabilizes the mitochondrial compartment to induce apoptosis. These events are also associated with secondarily lysosomal membrane permeabilization and activation of caspase-8, mediated by activation of cathepsins and calpains. This leads to the generation of truncated tBid and further disruption of the mitochondrial homeostasis. The disruption of lysosomal homeostasis lead to TFEB delocalization to the nuclei that allow lysosome biogenesis and autophagy stimulation. These two pathways of uneven intensity and momentum converge towards an amplification of cell death that still has to be depicted in more details.

It has been suggested that it may be possible to exploit autophagy for cancer therapy. Indeed, there is a complex interplay involving early autophagy, as soon as mitochondria produce superoxide anions and hydrogen peroxide. At 10 μM curcumin, there are evidences of autophagosomes whereas only early events of apoptosis are detectable. The initial autophagy induction has been efficiently depicted by the silmultaneous use of impedancemetry and multiparameric flow cytometry, i.e. mitochondrial membrane potential, superoxide anions production and calcium levels. Autophagy was also depicted indirectly by acidic vesicles staining as well as cell cycle analysis and together with electron microscopy for mitochondrial swelling and autophagosome formation.

We found that the production of reactive oxygen species and formation of autophagosomes following curcumin treatment was almost completely blocked at different levels by each of N-acetylcystein, MitoQ10 and SKQ1 (mitochondrial targeted antioxidants), calcium chelators, and the mitochondrial calcium uniport inhibitor, ruthenium red. Curcumin-induced autophagy failed to rescue all cells since a majority of cells underwent a type II cell death following the initial autophagic processes. However, a small amount of cells which where blocked into the cell cycle, escape at a 10 to 20 μM curcumin concentration and are rescued to give rise to a novel cellular proliferation phase. Thus, curcumin act as a valuable tool to study the fine and dynamic balance between oxidative stress, autophagy, and apoptosis.


Bioblast editor: Plangger M, Tindle-Solomon L


Labels: MiParea: Pharmacology;toxicology  Pathology: Cancer  Stress:Cell death 






Affiliations

Saints-Pères Inst Neurosciences, Mitochondria, apoptosis and autophagy, Paris, France.