Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP

Seo, Bo Ram; Min, Kyoung‐jin; Woo, Seon Min; Choe, Mi Sun; Choi, Kyeong Sook; Lee, Young-Kyung; Yoon, Gyesoon; Kwon, Taeg Kyu

doi:10.1089/ars.2016.6749

Cited by 40 publications

(43 citation statements)

References 38 publications

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“…First, ROS induces expression levels of Cbl, E3 ligase of c-FLIP. Seo et al, reported that inhibition of cathepsin S induced down-regulation of c-FLIP expression through up-regulation of Cbl expression in a ROS-dependent manner [69] . Second, ROS induces phosphorylation and ubiquitination of c-FLIP.…”

Section: Discussionmentioning

confidence: 99%

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Seo

Kim

et al. 2017

Redox Biology

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Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.

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Section: Discussionmentioning

confidence: 99%

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Seo

Kim

et al. 2017

Redox Biology

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“…Zhu et al () investigated the effect of Septin4_i 1 on LX‐2 cells and observed decreased expression in p‐AKT and Bcl‐2 and an increased expression in cleaved caspase‐3, key molecules in the apoptotic pathways. Previous studies have reported that the inhibition of PI3K/AKT activated the transcription factor Fox‐o1, reducing cellular‐FLICE inhibitory protein (c‐FLIP) expression and, consequently, activating caspases ‐3 and ‐8, cytochrome c, and Bid (Seo et al, ). Moreover, the Fox‐o1 knockdown restores the c‐FLIP expression, resulting in increased apoptosis resistance in LX‐2 cells through the pathway induced by the protein TRAIL (Park et al, ).…”

Section: Cellular Apoptosis and Its Correlation With Hepatic Fibrosismentioning

confidence: 99%

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Silva

Ramos

Moraes

2017

Cell Biology International

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Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.

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“…In our study, one mechanism of angelicin‐mediated TRAIL sensitization is down‐regulation of c‐FLIP expression. Our group also reported that combined treatment with thioridazine and curcumin induced down‐regulation of c‐FLIP through up‐regulation of ROS‐mediated PSMA5 expression (Seo, Kim, et al, ). In addition, inhibition of cathepsin S induced down‐regulation of c‐FLIP expression via up‐regulation of Cbl expression in a ROS dependent manner (Seo, Min, et al, ).…”

Section: Discussionmentioning

confidence: 89%

Angelicin potentiates TRAIL‐induced apoptosis in renal carcinoma Caki cells through activation of caspase 3 and down‐regulation of c‐FLIP expression

Min

Seo

et al. 2017

Drug Development Research

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Preclinical Research & Development Angelicin is a furocoumarin derived from Psoralea corylifolia L. fruit that has anti-inflammatory and anti-tumor activity. In the present study, the effect of angelicin in enhancing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptotic cell death was studied in Caki (renal carcinoma) cells. Angelicin alone and TRAIL alone had no effect on apoptosis, but in combination these compounds markedly induced apoptosis in the cancer cell lines while not inducing apoptosis in normal cells. The combination treatment induced accumulation of the sub-G1 population, DNA fragmentation, and activated caspase 3 activity in Caki cells, induced down-regulation of c-FLIP expression post-translationally, and over-expression of c-FLIP markedly blocked apoptosis induced by combined treatment with angelicin plus TRAIL. This study provides evidence that angelicin might be a TRAIL sensitizer.

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Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP

Abstract: Our results indicated that inhibition of cathepsin S stimulates TRAIL-induced apoptosis through downregulation of Bcl-2 and Cbl-mediated c-FLIP by ROS-mediated p53 expression. Antioxid. Redox Signal. 27, 215-233.

Cited by 40 publications

References 38 publications

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Angelicin potentiates TRAIL‐induced apoptosis in renal carcinoma Caki cells through activation of caspase 3 and down‐regulation of c‐FLIP expression

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