Apigeninidin induces apoptosis through activation of Bak and Bax and subsequent mediation of mitochondrial damage in human promyelocytic leukemia HL-60 cells

Apoptosis can be thought of as a signalling cascade that results in the death of the cell. Properly executed apoptosis is critically important for both development and homoeostasis of most animals. Accordingly, defects in apoptosis can contribute to the development of autoimmune disorders, neurological diseases and cancer. Broadly speaking, there are two main pathways by which a cell can engage apoptosis: the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which, in addition to its role as the bioenergetic centre of the cell, is also the cell's reservoir of pro-death factors which reside in the mitochondrial IMS (intermembrane space). During intrinsic apoptosis, pores are formed in the OMM (outer mitochondrial membrane) of the mitochondria in a process termed MOMP (mitochondrial outer membrane permeabilization). This allows for the release of IMS proteins; once released during MOMP, some IMS proteins, notably cytochrome c and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI), promote caspase activation and subsequent cleavage of structural and regulatory proteins in the cytoplasm and the nucleus, leading to the demise of the cell. MOMP is achieved through the co-ordinated actions of pro-apoptotic members and inhibited by anti-apoptotic members of the Bcl-2 family of proteins. Other aspects of mitochondrial physiology, such as mitochondrial bioenergetics and dynamics, are also involved in processes of cell death that proceed through the mitochondria. Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole.

Intermembrane space

Intrinsic apoptosis

Apoptosome

Mitochondrial apoptosis-induced channel

10.1042/bse0470099

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Citations (160)

Mitochondria and apoptosis regulation

Shengming kexue (2008)

Zhu Yu-shan

Apoptosis is a highly regulated form of programmed cell death,which plays a key role in the development and homeostasis of multicellular organisms.Mitochondria play a central role in the regulation of apoptotic cell death.Upon death stimuli,different apoptogenic factors such as cytochrome c and Smac/Diablo are released during the early stages of apoptosis.A small amount cytochrome c may be sufficient for activating caspases.Once activated,caspases can positively feedback to attack mitochondria leading to a more profound loss of cytochrome c and consequently mitochondrial dysfunction.This caspase-mediated late stage of cyto- chrome c release causes the complete disruption of mitochondrial electron transport chain,leading to the increase in cellular ROS and complete loss of ATP generation,late stage of apoptotic events or secondary necrosis.Bcl-2 and its family proteins are important for regulating cytochrome c release and apoptotic processes.

Apoptosome

Intrinsic apoptosis

Mitochondrial apoptosis-induced channel

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Possible involvement of caspase activation in nitric oxide-induced neuronal apoptosis in SH-SY5Y cells

Folia Pharmacologica Japonica (1998)

Takashi Uehara Yasuyuki Nomura

We here report involvement of caspases in NO-induced neuronal apoptosis. Our experiments were designed to elucidate how NO induces neuronal cell death using NOC18, a new type of NO donor that spontaneously releases NO alone, without enzymatic metabolization. NOC18 induced apoptosis in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner estimated with DNA fragmentation assay, FACScan analysis, and nuclear morphology. In this study, oxyhemoglobin, an NO trapper, suppressed NOC18-triggered DNA fragmentation, indicating that NO from NOC18 is an apoptosis-inducer. An increase in caspase-3-like protease activity was observed in parallel with the induction of apoptosis, but no caspase-1-like protease activity was detected. The level of pro-caspase-2 protein, a precursor of caspase-2, was decreased dramatically. In addition, NOC18 also caused the cleavage of PARP, yielding an 85 kDa protein, a typical fragment of the caspases reaction. Oxyhemoglobin blocked the decrease in pro-caspase-2 and the cleavage of PARP by NOC18. Moreover, NO elicited the release of cytochrome c into the cytosol from mitochondria during apoptosis. These results suggest that activation of caspases by cytochrome c released from mitochondria is involved in neuronal apoptosis induced by NO.

SH-SY5Y

Intrinsic apoptosis

Caspase-9

Fragmentation

Apoptotic DNA fragmentation

10.1254/fpj.112.supplement_118

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Citations (3)

Antiproliferative activity of the total saponin of Solanum lyratum Thunb in Hela cells by inducing apoptosis.

PubMed (2008)

Haoran Liu Xiangdong Peng Haibo He Yuhong Wang Ya Li

Total saponin of Solanum lyratum Thunb (TSSLT), a species of natural biologically active substances isolated from Solanum lyratum Thunb, possesses various bioactivities. It has been proposed that the induction of apoptosis may be the basis of its antitumor activity. However, the molecular mechanism underlying the total saponin-induced apoptotic process remains unknown. In the present study, we describe the anti-proliferative effect of TSSLT on human cervical cancer cells (Hela). The TSSLT induced apoptosis of Hela in a time-dependent manner with an IC50 for cell viability of 6 microg/ml. The TSSLT-induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-like activities, poly (ADP-ribose) polymerase (PARP) cleavage and release of cytochrome c (cyt c) into cytosol. TSSLT activated various caspases such as caspase-3, -8, and -9 (like) activities but not caspase-1 like activity. The cell death was completely prevented by the pan caspase inhibitor benzyloxy carbonyl-Val-Ala-Asp- fluoromethyl-ketone (Z-VAD-FMK). More than 80% cell survival was observed in the presence of a caspase-3 inhibitor. In addition, treatment with TSSLT induced the increase of Bax:Bcl-2 ratio in Hela cells. These results suggest that the induction of apoptosis by TSSLT involves multiple pathways antigen including death receptor and mitochondrial pathway and strongly suggest that the mitochondrial pathway was mediated by low expression of Bcl-2 and upregulation of Bax, release of cyt c and subsequent activation of caspase-3 followed by down stream events leading to apoptotic cell death.

HeLa

Viability assay

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Citations (12)

Hydrostatic Pressure Induces Apoptosis in the Human Leukaemic T‐Cell Line Jurkat Via the Mitochondrial Pathway

Scandinavian Journal of Immunology (2004)

Mariana Klett E-M Boneberg Kristina Trenz Rolf Knippers Harald Illges

Abstract We investigated the effect of pressure levels ranging from 80 to 500 bar on the proliferative capacity and viability of Jurkat leukaemic T cells. Pressurization at 360 bar induced apoptotic cell death as shown by apoptotic morphology after Hoechst staining, DNA fragmentation in the TdT‐mediated dUTP nick end labelling‐assay and cleavage of several caspase substrates. Cell death could be prevented by the general caspase inhibitor zVAD‐fmk. Breakdown of the mitochondrial membrane potential and the release of cytochrome c provided strong evidence for an involvement of the mitochondrial pathway, whereas a central role of the death receptor pathway was excluded because caspase‐8 was not significantly activated. Pressure incubation led to calcium influx after 5 min, and we hypothesize that calcium influx could be the primary trigger for pressure‐induced apoptosis.

Jurkat cells

Hydrostatic pressure

Apoptotic DNA fragmentation

Fragmentation

Mitochondrial apoptosis-induced channel

Viability assay

10.1111/j.0300-9475.2004.01496.x

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Citations (2)

Renal carcinoma cells undergo apoptosis without oligonucleosomal DNA fragmentation

Biochemical and Biophysical Research Communications (2004)

Kanako Yamaguchi