• Asian Pacific Journal of Cancer Prevention
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• 제16권6호
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• pp.2129-2144
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• 2015

Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

• Biomolecules & Therapeutics
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• 제27권1호
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• pp.41-47
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• 2019

The apoptotic effects of shikonin (5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methylpent-3-enyl]naphthalene-1,4-dione) on the human colon cancer cell line SNU-407 were investigated in this study. Shikonin showed dose-dependent cytotoxic activity against SNU-407 cells, with an estimated $IC_{50}$ value of $3{\mu}M$ after 48 h of treatment. Shikonin induced apoptosis, as evidenced by apoptotic body formation, sub-G_1$ phase cells, and DNA fragmentation. Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members, and the apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress, leading to activation of the $PERK/elF2{\alpha}/CHOP$ apoptotic pathway, and mitochondrial $Ca^{2+}$ accumulation. Shikonin increased mitochondrial membrane depolarization and altered the levels of apoptosis-related proteins, with a decrease in B cell lymphoma (Bcl)-2 and an increase in Bcl-2-associated X protein, and subsequently, increased expression of cleaved forms of caspase-9 and -3. Taken together, we suggest that these mechanisms, including MAPK signaling and the ER- and mitochondria-mediated pathways, may underlie shikonin-induced apoptosis related to its anticancer effect.

• Journal of Yeungnam Medical Science
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• 제34권2호
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• pp.174-181
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• 2017

Ferroptosis is a newly recognized type of cell death that results from iron-dependent lipid peroxidation and is different from other types of cell death, such as apoptosis, necrosis, and autophagic cell death. This type of cell death is characterized by mitochondrial shrinkage with an increased mitochondrial membrane density and outer mitochondrial membrane rupture. Ferroptosis can be induced by a loss of activity of system $X_c{^-}$ and the inhibition of glutathione peroxidase 4, followed by the accumulation of lipid reactive oxygen species (ROS). In addition, inactivation of the mevalonate and transsulfuration pathways is involved in the induction of ferroptosis. Moreover, nicotinamide adenine dinucleotide phosphate oxidase and p53 promote ferroptosis by increasing ROS production, while heat shock protein beta-1 and nuclear factor erythroid 2-related factor 2 inhibit ferroptosis by reducing iron uptake. This article outlines the molecular mechanisms and signaling pathways of ferroptosis regulation, and explains the roles of ferroptosis in human disease.

• BMB Reports
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• 제35권1호
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• pp.24-27
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• 2002

Apoptotic cell death is an active process mediated by various signaling pathways, which include the caspase cascade and the stress-activated protein kinase pathways. The caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria. Activation of the route from cell surface requires the cellular components that include membrane receptors, adaptor proteins such as TRADD and FADD, and caspase-8, while activation of the other from mitochondria requires Apaf-1, caspase-9, and cytosolic cytochrome c. On the other hand, persistent stimulation of the stress-activated protein kinase pathway is also shown to mediate apoptosis in many cell types. Gene-targeting studies with jnk- or jip-null mice, in particular, strongly suggest that this signaling pathway plays a pivotal role in the cellular machinery for apoptosis.

• BMB Reports
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• 제38권6호
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• pp.639-645
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• 2005

Protein kinase C (PKC) isozymes, a family of serine-threonine kinases, are important regulators of cell proliferation and malignant transformation. Phorbol esters, the prototype PKC activators, cause PKC translocation to the plasma membrane in prostate cancer cells, and trigger an apoptotic response. Studies in recent years have determined that each member of the PKC family exerts different effects on apoptotic or survival pathways. $PKC{\delta}$, one of the novel PKCs, is a key player of the apoptotic response via the activation of the p38 MAPK pathway. Studies using RNAi revealed that depletion of $PKC{\delta}$ totally abolishes the apoptotic effect of the phorbol ester PMA. Activation of the classical $PKC{\alpha}$ promotes the dephosphorylation and inactivation of the survival kinase Akt. Studies have assigned a pro-survival role to $PKC{\varepsilon}$, but the function of this PKC isozyme remains controversial. Recently, it has been determined that the PKC apoptotic effect in androgen-dependent prostate cancer cells is mediated by the autocrine secretion of death factors. $PKC{\delta}$ stimulates the release of $TNF{\alpha}$ from the plasma membrane, and blockade of $TNF{\alpha}$ secretion or $TNF{\alpha}$ receptors abrogates the apoptotic response of PMA. Molecular analysis indicates the requirement of the extrinsic apoptotic cascade via the activation of death receptors and caspase-8. Dissecting the pathways downstream of PKC isozymes represents a major challenge to understanding the molecular basis of phorbol ester-induced apoptosis.

• 동의생리병리학회지
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• 제23권6호
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• pp.1449-1459
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• 2009

Coptidis rhizoma (huanglian) is an herb that is widely used in traditional Chinese medicine that has recently been shown to possess anticancer activity. However, the molecular mechanism underlying the anticancer effects of this herb is poorly understood. In this study, we investigated the anticancer activity of a combination of CR extract and arsenic trioxide, as well as the apoptotic pathway associated with its mechanism of action in human lung cancer H157 cells. Combined treatment of H157 cells with CR extract and arsenic trioxide resulted in significant apoptotic death. In addition, combined treatment with CR extract and arsenic trioxide acted in concert to induce a loss of mitochondrial membrane potential (${\Delta}{\Psi}$), the release of cytochrome c from mitochondria, and an increase in the expression of pro-apoptotic p53 and Bax protein, which resulted in activation of caspases and apoptosis. CR extract combined with arsenic trioxide also increased the lipid peroxidation, mRNA expression of DR4 and DR5 and caspase-8 activity. These data indicate that combined treatment with CR extract and arsenic trioxide enhanced apoptotic cell death in H157 cells through diverse pathways, including mitochondrial dysfunction and death receptors, particularly DR4 and DR5. Thus, this treatment may be an effective from of chemotherapy.

• Toxicological Research
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• 제22권1호
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• pp.31-37
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• 2006

It was previously found that melittin inhibited $NF-{\kappa}B$ activity by reacting with signal molecules of $NF-{\kappa}B$ which is critical contributor in cancer cell growth by induction of apoptotic cell death. We here investigated whether melittin inhibits cell growth of human prostate cancer cells through induction of apoptotic cell death, and the possible signal pathways. Melittin ($0{\sim}1\;{\mu}g/ml$) inhibited prostate cancer cell growth in a dose dependent manner. Conversely related to the growth inhibitory effect, melittin increased the induction of apoptotic cell death in a dose dependent manner. Melittin also inhibited DNA binding activity of $NF-{\kappa}B$, an anti-apoptotic transcriptional factor. Consistent with the induction of apoptotic cell death and inhibition of $NF-{\kappa}B$, melittin increased the expression of pro-apoptotic proteins caspase-3, and Bax but down-regulated anti-apoptotic protein Bcl-2. These findings suggest that melittin could inhibit prostate cancer cell growth, and this effect may be related with the induction of apoptotic cell death via inactivation of $NF-{\kappa}B$.

• The Korean Journal of Physiology and Pharmacology
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• 제26권6호
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• pp.447-456
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• 2022

The present study was carried out to investigate the effect of Arctigenin on cell growth and the mechanism of cell death elicited by Arctigenin were examined in FaDu human pharyngeal carcinoma cells. To determine the apoptotic activity of Arctigenin in FaDu human pharyngeal carcinoma cells, cell viability assay, DAPI staining, caspase activation analysis, and immunoblotting were performed. Arctigenin inhibited the growth of cells in a dose-dependent manner and induced nuclear condensation and fragmentation. Arctigenin-treated cells showed caspase-3/7 activation and increased apoptosis versus control cells. FasL, a death ligand associated with extrinsic apoptotic signaling pathways, was up-regulated by Arctigenin treatment. Moreover, caspase-8, a part of the extrinsic apoptotic pathway, was activated by Arctigenin treatments. Expressions of anti-apoptotic factors such as Bcl-2 and Bcl-xL, components of the mitochondria-dependent intrinsic apoptosis pathway, significantly decreased following Arctigenin treatment. The expressions of pro-apoptotic factors such as BAX, BAD and caspase-9, and tumor suppressor -53 increased by Arctigenin treatments. In addition, Arctigenin activated caspase-3 and poly (ADP-ribose) polymerase (PARP) induced cell death. Arctigenin also inhibited the proliferation of FaDu cells by the suppression of p38, NF-κB, and Akt signaling pathways. These results suggest that Arctigenin may inhibit cell proliferation and induce apoptotic cell death in FaDu human pharyngeal carcinoma cells through both the mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway.

• Molecules and Cells
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• 제27권5호
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• pp.533-538
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• 2009

Heat shock protein 27 (Hsp27) is a molecular chaperone protein which regulates cell apoptosis by interacting directly with the caspase activation components in the apoptotic pathways. With the assistance of the Tat protein transduction domain we directly delivered the Hsp27 into the myocardial cell line, H9c2 and demonstrate that this protein can reverse hypoxia-induced apoptosis of cells. In order to characterize the contribution of Hsp27 in blocking the two major apoptotic pathways operational within cells, we exposed H9c2 cells to staurosporine and cobalt chloride, agents that induce mitochondria-dependent (intrinsic) and -independent (extrinsic) pathways of apoptosis in cells respectively. The Tat-Hsp27 fusion protein showed a greater propensity to inhibit the effect induced by the cobalt chloride treatment. These data suggest that the Hsp27 predominantly exerts its protective effect by interfering with the components of the extrinsic pathway of apoptosis.

• BMB Reports
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• 제52권2호
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• pp.119-126
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• 2019

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.