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Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events

View Article: PubMed Central - PubMed

ABSTRACT

Curcumin, a major active component of turmeric (Curcuma longa, L.), has anticancer effects. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying these effects is still unclear. Here, we investigated the mechanisms leading to apoptosis in curcumin-treated cells. Curcumin induced endoplasmic reticulum stress causing calcium release, with a destabilization of the mitochondrial compartment resulting in apoptosis. These events were also associated with lysosomal membrane permeabilization and of caspase-8 activation, mediated by cathepsins and calpains, leading to Bid cleavage. Truncated tBid disrupts mitochondrial homeostasis and enhance apoptosis. We followed the induction of autophagy, marked by the formation of autophagosomes, by staining with acridine orange in cells exposed curcumin. At this concentration, only the early events of apoptosis (initial mitochondrial destabilization with any other manifestations) were detectable. Western blotting demonstrated the conversion of LC3-I to LC3-II (light chain 3), a marker of active autophagosome formation. We also found that the production of reactive oxygen species and formation of autophagosomes following curcumin treatment was almost completely blocked by N-acetylcystein, the mitochondrial specific antioxidants MitoQ10 and SKQ1, the calcium chelators, EGTA-AM or BAPTA-AM, and the mitochondrial calcium uniporter inhibitor, ruthenium red. Curcumin-induced autophagy failed to rescue all cells and most cells underwent type II cell death following the initial autophagic processes. All together, these data imply a fail-secure mechanism regulated by autophagy in the action of curcumin, suggesting a therapeutic potential for curcumin. Offering a novel and effective strategy for the treatment of malignant cells.

No MeSH data available.


Schematic representation of curcumin effects. Curcumin mainly targets the ER and lysosomes but to a different extent. The classic apoptotic pathway is mediated by calcium release from the ER. Uptake of this calcium by mitochondria disrupts mitochondrial homeostasis. Calcium alters mitochondrial electron transport causing substantial ROS production (both superoxide anions and hydrogen peroxide), which leads to the opening of the permeability transition pore in the mitochondrial membrane. Consequently, cytochrome c is released and the caspase-9 and -3/7 pathway is activated leading to cell death (mostly by apoptosis). Furthermore, the ER stress pathway leads to the formation of autophagic vacuoles that attempt to eliminate the dysfunctional mitochondria. The cleavage of Beclin-1 is associated with apoptosis and leads to the accumulation of autophagic vacuoles. Despite the activation of autophagy, cells undergo necrotic cell death following these initial apoptotic events. A lysosomal pathway may also be active. Curcumin destabilizes lysosomal membranes leading to lysosomal membrane permeability and the activation of both cathepsins and chemotrypsins. Activated caspase-8 leads to Beclin-1 cleavage. The increase in cytosolic calcium concentrations activates calpains that contribute to the degradation process and accelerate cell death. The various inhibitors used in this work are indicated with the pathways they affect. Curcumin interacts with the ER and lysosomes.
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fig9: Schematic representation of curcumin effects. Curcumin mainly targets the ER and lysosomes but to a different extent. The classic apoptotic pathway is mediated by calcium release from the ER. Uptake of this calcium by mitochondria disrupts mitochondrial homeostasis. Calcium alters mitochondrial electron transport causing substantial ROS production (both superoxide anions and hydrogen peroxide), which leads to the opening of the permeability transition pore in the mitochondrial membrane. Consequently, cytochrome c is released and the caspase-9 and -3/7 pathway is activated leading to cell death (mostly by apoptosis). Furthermore, the ER stress pathway leads to the formation of autophagic vacuoles that attempt to eliminate the dysfunctional mitochondria. The cleavage of Beclin-1 is associated with apoptosis and leads to the accumulation of autophagic vacuoles. Despite the activation of autophagy, cells undergo necrotic cell death following these initial apoptotic events. A lysosomal pathway may also be active. Curcumin destabilizes lysosomal membranes leading to lysosomal membrane permeability and the activation of both cathepsins and chemotrypsins. Activated caspase-8 leads to Beclin-1 cleavage. The increase in cytosolic calcium concentrations activates calpains that contribute to the degradation process and accelerate cell death. The various inhibitors used in this work are indicated with the pathways they affect. Curcumin interacts with the ER and lysosomes.

Mentions: These events are summarized in Figure 9. Curcumin inserts into the ER and lysosomal membrane. Calcium is rapidly released as a result of ER stress, and strongly promotes mitochondrial destabilization, involving the production of superoxide anions and H2O2, mitochondrial membrane alterations and bioenergetic changes. These events promote MMP and cytochrome c release followed by the activation of executive caspases. However, at low curcumin concentrations and early during this sequence of events, curcumin induces autophagic ‘survival’ processes, which attempt to discard nonfunctional mitochondria and save cells from further destruction. However, if the initial crosstalk between apoptosis and autophagy is unsuccessful, a third pathway leads to cell death. In this case, LMP results in the release of cathepsins which activate caspase-8 and -3/9, to guarantee the destruction of cells.


Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events
Schematic representation of curcumin effects. Curcumin mainly targets the ER and lysosomes but to a different extent. The classic apoptotic pathway is mediated by calcium release from the ER. Uptake of this calcium by mitochondria disrupts mitochondrial homeostasis. Calcium alters mitochondrial electron transport causing substantial ROS production (both superoxide anions and hydrogen peroxide), which leads to the opening of the permeability transition pore in the mitochondrial membrane. Consequently, cytochrome c is released and the caspase-9 and -3/7 pathway is activated leading to cell death (mostly by apoptosis). Furthermore, the ER stress pathway leads to the formation of autophagic vacuoles that attempt to eliminate the dysfunctional mitochondria. The cleavage of Beclin-1 is associated with apoptosis and leads to the accumulation of autophagic vacuoles. Despite the activation of autophagy, cells undergo necrotic cell death following these initial apoptotic events. A lysosomal pathway may also be active. Curcumin destabilizes lysosomal membranes leading to lysosomal membrane permeability and the activation of both cathepsins and chemotrypsins. Activated caspase-8 leads to Beclin-1 cleavage. The increase in cytosolic calcium concentrations activates calpains that contribute to the degradation process and accelerate cell death. The various inhibitors used in this work are indicated with the pathways they affect. Curcumin interacts with the ER and lysosomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4979459&req=5

fig9: Schematic representation of curcumin effects. Curcumin mainly targets the ER and lysosomes but to a different extent. The classic apoptotic pathway is mediated by calcium release from the ER. Uptake of this calcium by mitochondria disrupts mitochondrial homeostasis. Calcium alters mitochondrial electron transport causing substantial ROS production (both superoxide anions and hydrogen peroxide), which leads to the opening of the permeability transition pore in the mitochondrial membrane. Consequently, cytochrome c is released and the caspase-9 and -3/7 pathway is activated leading to cell death (mostly by apoptosis). Furthermore, the ER stress pathway leads to the formation of autophagic vacuoles that attempt to eliminate the dysfunctional mitochondria. The cleavage of Beclin-1 is associated with apoptosis and leads to the accumulation of autophagic vacuoles. Despite the activation of autophagy, cells undergo necrotic cell death following these initial apoptotic events. A lysosomal pathway may also be active. Curcumin destabilizes lysosomal membranes leading to lysosomal membrane permeability and the activation of both cathepsins and chemotrypsins. Activated caspase-8 leads to Beclin-1 cleavage. The increase in cytosolic calcium concentrations activates calpains that contribute to the degradation process and accelerate cell death. The various inhibitors used in this work are indicated with the pathways they affect. Curcumin interacts with the ER and lysosomes.
Mentions: These events are summarized in Figure 9. Curcumin inserts into the ER and lysosomal membrane. Calcium is rapidly released as a result of ER stress, and strongly promotes mitochondrial destabilization, involving the production of superoxide anions and H2O2, mitochondrial membrane alterations and bioenergetic changes. These events promote MMP and cytochrome c release followed by the activation of executive caspases. However, at low curcumin concentrations and early during this sequence of events, curcumin induces autophagic ‘survival’ processes, which attempt to discard nonfunctional mitochondria and save cells from further destruction. However, if the initial crosstalk between apoptosis and autophagy is unsuccessful, a third pathway leads to cell death. In this case, LMP results in the release of cathepsins which activate caspase-8 and -3/9, to guarantee the destruction of cells.

View Article: PubMed Central - PubMed

ABSTRACT

Curcumin, a major active component of turmeric (Curcuma longa, L.), has anticancer effects. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying these effects is still unclear. Here, we investigated the mechanisms leading to apoptosis in curcumin-treated cells. Curcumin induced endoplasmic reticulum stress causing calcium release, with a destabilization of the mitochondrial compartment resulting in apoptosis. These events were also associated with lysosomal membrane permeabilization and of caspase-8 activation, mediated by cathepsins and calpains, leading to Bid cleavage. Truncated tBid disrupts mitochondrial homeostasis and enhance apoptosis. We followed the induction of autophagy, marked by the formation of autophagosomes, by staining with acridine orange in cells exposed curcumin. At this concentration, only the early events of apoptosis (initial mitochondrial destabilization with any other manifestations) were detectable. Western blotting demonstrated the conversion of LC3-I to LC3-II (light chain 3), a marker of active autophagosome formation. We also found that the production of reactive oxygen species and formation of autophagosomes following curcumin treatment was almost completely blocked by N-acetylcystein, the mitochondrial specific antioxidants MitoQ10 and SKQ1, the calcium chelators, EGTA-AM or BAPTA-AM, and the mitochondrial calcium uniporter inhibitor, ruthenium red. Curcumin-induced autophagy failed to rescue all cells and most cells underwent type II cell death following the initial autophagic processes. All together, these data imply a fail-secure mechanism regulated by autophagy in the action of curcumin, suggesting a therapeutic potential for curcumin. Offering a novel and effective strategy for the treatment of malignant cells.

No MeSH data available.