Abstract
BackgroundAnnonaceous acetogenins are a family of natural products with antitumor activities. Annonaceous acetogenin mimic AA005 reportedly inhibits mammalian mitochondrial NADH-ubiquinone reductase (Complex I) and induces gastric cancer cell death. However, the mechanisms underlying its cell-death-inducing activity are unclear.MethodsWe used SW620 colorectal adenocarcinoma cells to study AA005 cytotoxic activity. Cell deaths were determined by Trypan blue assay and flow cytometry, and related proteins were characterized by western blot. Immunofluorescence and subcellular fractionation were used to evaluate AIF nuclear translocation. Reactive oxygen species were assessed by using redox-sensitive dye DCFDA.ResultsAA005 induces a unique type of cell death in colorectal adenocarcinoma cells, characterized by lack of caspase-3 activation or apoptotic body formation, sensitivity to poly (ADP-ribose) polymerase inhibitor Olaparib (AZD2281) but not pan-caspase inhibitor Z-VAD.fmk, and dependence on apoptosis-inducing factor (AIF). AA005 treatment also reduced expression of mitochondrial Complex I components, and leads to accumulation of intracellular reactive oxygen species (ROS) at the early stage. Blocking ROS formation significantly suppresses AA005-induced cell death in SW620 cells. Moreover, blocking activation of RIP-1 by necroptosis inhibitor necrotatin-1 inhibits AIF translocation and partially suppresses AA005-induced cell death in SW620 cells demonstrating that RIP-1 protein may be essential for cell death.ConclusionsAA005 may trigger the cell death via mediated by AIF through caspase-3 independent pathway. Our work provided new mechanisms for AA005-induced cancer cell death and novel clues for cancer treatment via AIF dependent cell death.
Highlights
Annonaceous acetogenins are a family of natural products with antitumor activities
AA005 induces cell death in various cancer cell lines To evaluate the potential cytotoxicity of annonaceous acetogenins (AAs) mimic AA005 (Figure 1A) [19], we administered AA005 to colorectal adenocarcinoma cell line SW620, breast cancer cell line BT-549, acute promyelocytic leukemia cell line NB4, and acute myelomonocytic leukemic cell line U937, followed by cell viability analysis with trypan-blue exclusion assays
AA005 induces non-canonical apoptosis To investigate the biochemical and morphological changes during the process of AA005-induced cell death, SW620 cells were treated with AA005, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) [20], and camptothecin [21]
Summary
Annonaceous acetogenins are a family of natural products with antitumor activities. Mitochondria can release apoptosisinducing factor (AIF) to initiate caspase-independent cell death [8,9]. The mitochondrial flavoprotein AIF is a caspase-independent cell-death-inducing factor [10]. During apoptotic signaling without caspase-3 activation, AIF is released from the mitochondria when the mitochondrial membrane is permeabilized, translocates to the nucleus where it induces cell death by triggering chromatin condensation and large-scale DNA fragmentation into ~50-kilobase strands with the help of other proteins such as Endo G (C. elegans), CypA (mice) or FEN-1 [10,11,12,13,14,15,16,17]. Our work may provide novel therapeutic clues for treating cancers via a non-canonical apoptotic pathway
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