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.
Mitochondria play a pivotal role in apoptosis in multicellular organisms by releasing apoptogenic factors such as cytochrome c that activate the caspases effector pathway, and apoptosis-inducing factor (AIF) that is involved in a caspase-independent cell death pathway. Here we report that cell death in the single-celled organism Dictyostelium discoideum involves early disruption of mitochondrial transmembrane potential (⌬⌿m) that precedes the induction of several apoptosis-like features, including exposure of the phosphatidyl residues at the external surface of the plasma membrane, an intense vacuolization, a fragmentation of DNA into large fragments, an autophagy, and the release of apoptotic corpses that are engulfed by neighboring cells. We have cloned a Dictyostelium homolog of mammalian AIF that is localized into mitochondria and is translocated from the mitochondria to the cytoplasm and the nucleus after the onset of cell death. Cytoplasmic extracts from dying Dictyostelium cells trigger the breakdown of isolated mammalian and Dictyostelium nuclei in a cell-free system, and this process is inhibited by a polyclonal antibody specific for Dictyostelium discoideum apoptosis-inducing factor (DdAIF), suggesting that DdAIF is involved in DNA degradation during Dictyostelium cell death. Our findings indicate that the cell death pathway in Dictyostelium involves mitochondria and an AIF homolog, suggesting the evolutionary conservation of at least part of the cell death pathway in unicellular and multicellular organisms. INTRODUCTIONProgrammed cell death (PCD) is a genetically regulated physiological process of cell suicide that is central to the development and homeostasis of multicellular organisms (Raff, 1992;Steller, 1995;Jacobson et al., 1997;Vaux and Korsmeyer, 1999). The basic machinery that controls the onset of PCD in roundworms (Caenorhabditis elegans), insects (Drosophila melanogaster), and vertebrates (mammals) appears to be present in all cells, at all times. Crucial aspects of PCD appear to be conserved, including both the genes encoding the basic cell death machinery, and the morphological and biochemical features of apoptosis, the most frequent phenotype of PCD (Jacobson et al., 1997;Horvitz, 1999;Song and Steller, 1999;Vaux and Korsmeyer, 1999).Mitochondria play a pivotal role in PCD in mammalian cells, in particular through the permeabilization/disruption of their outer membrane, with (or followed by) the loss of mitochondrial transmembrane potential (⌬⌿m) (Kroemer et al., 1995;Green and Reed, 1998;Petit et al., 1998;Goldstein et al., 2000;Martinou et al., 2000), leading to the release of cytochrome c (Liu et al., 1996) and apoptosis-inducing factor # Corresponding author. E-mail address: pxpetit@zeus.cochin.inserm.fr. Abbreviations used: AIF, apoptosis-inducing factor; BSA, bovine serum albumin; DIF-1, differentiation-inducing factor-1; PCR, polymerase chain reaction; ⌬⌿m, mitochondrial transmembrane potential; PCD, programmed cell death; PPIX, protoporphyrin IX; PBS, phosphate-buffered saline. ©...
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