scholarly journals Hispidulin Enhances TRAIL-Mediated Apoptosis via CaMKKβ/AMPK/USP51 Axis-Mediated Bim Stabilization

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1960 ◽  
Author(s):  
Seon Min Woo ◽  
Seung Un Seo ◽  
Sang Hyun Kim ◽  
Ju-Ock Nam ◽  
Shin Kim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mesangial Cells ◽  
Critical Role ◽  
Combined Treatment ◽  
Carcinoma Cells ◽  
Human Skin Fibroblast ◽  
Human Carcinoma ◽  
Anti Cancer ◽  
Xenograft Models ◽  
Induced Apoptosis

Hispidulin, a natural compound present in herbs, has anti-cancer effects. Here, we investigated whether hispidulin sensitizes human carcinoma cells to apoptosis induced by TRAIL. Sub-lethal dosages of TRAIL alone and hispidulin alone does not increase apoptosis, but hispidulin increases sensitivity to TRAIL, resulting in induction of apoptosis in hispidulin plus TRAIL-treated cancer cells. In addition, combined treatment with hispidulin and TRAIL also reduced tumor growth and increased apoptosis in xenograft models. However, hispidulin did not alter cell viability in human renal normal mesangial cells and human skin fibroblast. Hispidulin markedly increased the BH3-only proteins Bim at the post-translational levels. Depletion of Bim with siRNA significantly blocked hispidulin plus TRAIL-induced apoptosis. Furthermore, we found that activation of AMPK by hispidulin has a crucial role in Bim proteins stability through up-regulation of USP51 expression. Our findings suggest that USP51-dependent stabilization of Bim by AMPK activation plays a critical role in hispidulin-mediated sensitization of cancer cells to apoptosis induced by TRAIL.

scholarly journals WP1130 Enhances TRAIL-Induced Apoptosis through USP9X-Dependent miR-708-Mediated Downregulation of c-FLIP

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 344 ◽  
Author(s):  
Seok Kim ◽  
Seon Woo ◽  
Kyoung-jin Min ◽  
Seung Seo ◽  
Tae-Jin Lee ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Mesangial Cells ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Carcinoma Cells ◽  
Human Mesangial Cells ◽  
Dub Inhibitor ◽  
Induced Apoptosis ◽  
Sensitizing Effect ◽  
Human Renal Carcinoma

WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and TRAIL significantly induced apoptosis in renal carcinoma, lung carcinoma and hepatocellular carcinoma cells, but not in normal cells (human mesangial cells (MC) and normal mouse kidney cells (TCMK-1)). The downregulation of c-FLIP protein expression was involved in combined treatment-induced apoptosis. WP1130-induced c-FLIP downregulation was regulated by microRNA (miR)-708 upregulation via inhibition of USP9X. Interestingly, knockdown of USP9X markedly induced c-FLIP downregulation, upregulation of miR-708 expression and sensitivity to TRAIL. Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment. In sum, WP1130 sensitized TRAIL-induced apoptosis through miR-708-mediated downregulation of c-FLIP by inhibition of USP9X.

scholarly journals Induction of apoptosis in RL95-2 human endometrial cancer cells by combination treatment with docosahexaenoic acid and triacsin C

2021 ◽  
Author(s):  
Soo‐Ho Chung ◽  
Hea-Hyeog Lee ◽  
Yeon-Suk Kim ◽  
Kisung Song ◽  
Tae-Hee Kim
Keyword(s):  
Endometrial Cancer ◽  
Docosahexaenoic Acid ◽  
Endometrial Carcinoma ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Combined Treatment ◽  
Carcinoma Cells ◽  
Tumour Development ◽  
Triacsin C ◽  
Induced Apoptosis

IntroductionDocosahexaenoic acid (DHA) supplementation has been reported to negatively correlate with cancer cell proliferation and tumour development in many cancer types. Although cumulative evidence has demonstrated the apoptotic effect and cytotoxicity of DHA against tumour development in many cell types, the precise cellular and biochemical mechanisms of DHA-induced apoptosis in human endometrial cancer cells have not been investigated.Material and methodsMTT assay was performed to confirm the degree of apoptosis by combining treatment with DHA and triacsin C in endometrial cancer cell line. The synergistic effects of triacsin C and DHA were identified by performing flowcytometry and immunoblotting analysis.ResultsCombined treatment with DHA and triacsin C significantly induced apoptosis in RL95-2 endometrial carcinoma cells. Combined treatment with 125 μM DHA and 5 μM triacsin C significantly increased the sub-G1 population and apoptotic fragments in endometrial carcinoma cells. It was also demonstrated that DHA and triacsin C induced apoptosis through mitochondrial pathways via caspases-9, -3, and -7 as well as through the extrinsic pathway by activation of caspase-8/BID.ConclusionsFurther elucidation of the apoptotic mechanisms involving DHA treatment with ACS ablation could shed light on possible new treatment strategies for endometrial cancer. In addition, further research into the mechanisms of DHA and triacsin C-induced apoptotic mechanisms may lead to the development of therapeutic strategies for endometrial cancer.

scholarly journals CHOP Is Involved in Endoplasmic Reticulum Stress-induced Apoptosis by Enhancing DR5 Expression in Human Carcinoma Cells

2004 ◽  
Vol 279 (44) ◽  
pp. 45495-45502 ◽  
Author(s):  
Hirohito Yamaguchi ◽  
Hong-Gang Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Human Cancer ◽  
Carcinoma Cells ◽  
Human Carcinoma ◽  
Human Cancer Cells ◽  
Induced Apoptosis ◽  
Hct116 Cells

It has been shown that excess stress to the endoplasmic reticulum (ER) triggers apoptosis, but the mechanisms underlying these processes remain unclear. We and others have reported previously that DR5 expression is up-regulated in thapsigargin (THG)-treated human cancer cells. Here, we provide evidence that CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. In human colon cancer HCT116 cells, knockdown of DR5 by siRNA blocked THG-induced Bax conformational change along with caspase-3 activation and cell death. Moreover, inhibition of CHOP expression attenuated DR5 up-regulation and apoptosis induced by THG, whereas ectopic expression of DR5 restored the sensitivity of CHOP siRNA-transfected cells to THG-induced apoptosis. In addition to HCT116 cells, inhibition of CHOP or DR5 induction also attenuated THG-induced cell death in other cancer cell lines including LNCaP, A2780S, and DU145, indicating that CHOP and DR5 are critical for ER stress-mediated apoptosis in human carcinoma cells. Furthermore, we identified a potential CHOP-binding site in the 5′-flanking region of the DR5 gene. Mutation of this site abrogated the enhanced reporter activity in response to THG treatment. Together, our findings suggest that CHOP regulates ER stress-induced apoptosis, at least in part, through enhancing DR5 expression in some types of human cancer cells.

scholarly journals Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma

2019 ◽  
Vol 20 (13) ◽  
pp. 3253 ◽  
Author(s):  
Seon Min Woo ◽  
Kyoung-jin Min ◽  
Seung Un Seo ◽  
Shin Kim ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Renal Carcinoma ◽  
Apoptotic Cell ◽  
Survivin Expression ◽  
Human Skin Fibroblast ◽  
Cancer Drugs ◽  
Survivin Protein ◽  
Anti Cancer ◽  
Induced Apoptosis

R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.

scholarly journals Melatonin Suppresses the Expression of 45S Preribosomal RNA and Upstream Binding Factor and Enhances the Antitumor Activity of Puromycin in MDA-MB-231 Breast Cancer Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ji Hoon Jung ◽  
Eun Jung Sohn ◽  
Eun Ah Shin ◽  
Duckgue Lee ◽  
Bonglee Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ribosome Biogenesis ◽  
Breast Cancer Cells ◽  
Mrna Level ◽  
Critical Role ◽  
Combined Treatment ◽  
Immunofluorescence Assay ◽  
High Concentration ◽  
Induced Apoptosis

Since the dysregulation of ribosome biogenesis is closely associated with tumor progression, in the current study, the critical role of ribosome biogenesis related signaling was investigated in melatonin and/or puromycin induced apoptosis in MDA-MB-231 breast cancer cells. Despite its weak cytotoxicity, melatonin from 3 mM attenuated the expression of 45S pre-ribosomal RNA (pre-rRNA), UBF as a nucleolar transcription factor, and fibrillarin at mRNA level and consistently downregulated nucleolar proteins such as UBF and fibrillarin at protein level in MDA-MB-231 cells. Furthermore, immunofluorescence assay revealed that UBF was also degraded by melatonin in MDA-MB-231 cells. In contrast, melatonin attenuated the expression of survival genes such as Bcl-xL, Mcl-1, cyclinD1, and cyclin E, suppressed the phosphorylation of AKT, mTOR, and STAT3, and cleaved PARP and activated caspase 3 only at a high concentration of 12 mM. However, combined treatment of melatonin (3 mM) and puromycin (1 μM) synergistically inhibited viability, attenuated the expression of 45S pre-rRNA and UBF, and consistently downregulated UBF, XPO1 and IPO7, procaspase 3, and Bcl-xL in MDA-MB 231 cells. Overall, these findings suggest that melatonin can be a cancer preventive agent by combination with puromycin via the inhibition of 45S pre-rRNA and UBF in MDA-MB 231 breast cancer cells.

scholarly journals Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Gabriela Carrasco-Torres ◽  
Rafael Baltiérrez-Hoyos ◽  
Erik Andrade-Jorge ◽  
Saúl Villa-Treviño ◽  
José Guadalupe Trujillo-Ferrara ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Maleic Anhydride ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Malignant Tumors ◽  
Combined Treatment ◽  
Current Data ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.

Lobetyolin inhibits the proliferation of breast cancer cells via ASCT2 down-regulation-induced apoptosis

2021 ◽  
pp. 096032712110214
Author(s):  
Yansong Chen ◽  
Ye Tian ◽  
Gongsheng Jin ◽  
Zhen Cui ◽  
Wei Guo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Glutamine Metabolism ◽  
Down Regulation ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Glutamine Uptake

This study aimed to investigate the anti-cancer effect of lobetyolin on breast cancer cells. Lobetyolin was incubated with MDA-MB-231 and MDA-MB-468 breast cancer cells for 24 h. Glucose uptake and the mRNA expression of GLUT4 ( SLC2A4), HK2 and PKM2 were detected to assess the effect of lobetyolin on glucose metabolism. Glutamine uptake and the mRNA expression of ASCT2 ( SLC1A5), GLS1, GDH and GLUL were measured to assess the effect of lobetyolin on glutamine metabolism. Annexin V/PI double staining and Hoechst 33342 staining were used to investigate the effect of lobetyolin on cell apoptosis. Immunoblot was employed to estimate the effect of lobetyolin on the expression of proliferation-related markers and apoptosis-related markers. SLC1A5 knockdown with specific siRNA was performed to study the role of ASCT2 played in the anti-cancer effect of lobetyolin on MDA-MB-231 and MDA-MB-468 breast cancer cells. C-MYC knockdown with specific siRNA was performed to study the role of c-Myc played in lobetyolin-induced ASCT2 down-regulation. Myr-AKT overexpression was performed to investigate the role of AKT/GSK3β signaling played in lobetyolin-induced down-regulation of c-Myc and ASCT2. The results showed that lobetyolin inhibited the proliferation of both MDA-MB-231 and MDA-MB-468 breast cancer cells. Lobetyolin disrupted glutamine uptake via down-regulating ASCT2. SLC1A5 knockdown attenuated the anti-cancer effect of lobetyolin. C-MYC knockdown attenuated lobetyolin-caused down-regulation of ASCT2 and Myr-AKT overexpression reversed lobetyolin-caused down-regulation of both c-Myc and ASCT2. In conclusion, the present work suggested that lobetyolin exerted anti-cancer effect via ASCT2 down-regulation-induced apoptosis in breast cancer cells.

scholarly journals p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-related Apoptosis-inducing Ligand Expression

2019 ◽  
Author(s):  
Matharage Gayani Dilshara ◽  
Ilandarage Menu Neelaka Molagoda ◽  
Rajapaksha Gedara Prasad Tharanga Jayasooriya ◽  
Yung Hyun Choi ◽  
Cheol Park ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
Chimeric Antibody ◽  
Ros Production ◽  
Death Receptor 5 ◽  
Homologous Protein ◽  
Anti Cancer ◽  
Ligand Expression ◽  
Induced Apoptosis ◽  
Factor C

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

scholarly journals MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 150 ◽  
Author(s):  
Hyun Lim ◽  
Moon Park ◽  
Changmin Kim ◽  
Beomku Kang ◽  
Hyo-Sook Song ◽  
...  
Keyword(s):  
Er Stress ◽  
Critical Role ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
U937 Cells ◽  
Anti Cancer ◽  
Spatholobus Suberectus ◽  
Induced Apoptosis ◽  
Related Proteins

Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer.

scholarly journals Increased Expression of Death Receptors 4 and 5 Synergizes the Apoptosis Response to Combined Treatment with Etoposide and TRAIL

2000 ◽  
Vol 20 (1) ◽  
pp. 205-212 ◽  
Author(s):  
Spencer B. Gibson ◽  
Ryan Oyer ◽  
Aaron C. Spalding ◽  
Steven M. Anderson ◽  
Gary L. Johnson
Keyword(s):  
Epithelial Cell ◽  
Cancer Cells ◽  
Topoisomerase Ii ◽  
Combined Treatment ◽  
Death Receptor ◽  
Death Receptors ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Death Receptor Ligand ◽  
Induced Apoptosis

ABSTRACT Chemotherapeutic genotoxins induce apoptosis in epithelial-cell-derived cancer cells. The death receptor ligand TRAIL also induces apoptosis in epithelial-cell-derived cancer cells but generally fails to induce apoptosis in nontransformed cells. We show here that the treatment of four different epithelial cell lines with the topoisomerase II inhibitor etoposide in combination with TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) induces a synergistic apoptotic response. The mechanism of the synergistic effect results from the etoposide-mediated increase in the expression of the death receptors 4 (DR4) and 5 (DR5). Inhibition of NF-κB activation by expression of kinase-inactive MEK kinase 1(MEKK1) or dominant-negative IκB (ΔIκB) blocked the increase in DR4 and DR5 expression following etoposide treatment. Addition of a soluble decoy DR4 fusion protein (DR4:Fc) to cell cultures reduced the amount of etoposide-induced apoptosis in a dose-dependent manner. The addition of a soluble TNF decoy receptor (TNFR:Fc) was without effect, demonstrating the specificity of DR4 binding ligands in the etoposide-induced apoptosis response. Thus, genotoxin treatment in combination with TRAIL is an effective inducer of epithelial-cell-derived tumor cell apoptosis relative to either treatment alone.

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