scholarly journals Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 838 ◽  
Author(s):  
Seon Min Woo ◽  
Seung Un Seo ◽  
Peter Kubatka ◽  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Chinese Medicine ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Biological Effects ◽  
Ectopic Expression ◽  
Protein Levels ◽  
Anti Cancer ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Necrosis Factor

Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through downregulation of anti-apoptotic proteins survivin and c-FLIP. Ectopic expression of survivin and c-FLIP markedly abolished honokiol and TRAIL-induced apoptosis. Mechanistically, honokiol induced protein degradation of c-FLIP and survivin through STAMBPL1, a deubiquitinase. STAMBPL1 interacted with survivin and c-FLIP, resulted in reduction of ubiquitination. Knockdown of STAMBPL1 reduced survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibited honokinol-induced survivin and c-FLIP degradation. Our findings provided that honokiol could overcome TRAIL resistance through survivin and c-FLIP degradation induced by inhibition of STAMBPL1 expression.

scholarly journals Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

2004 ◽  
Vol 15 (7) ◽  
pp. 3266-3284 ◽  
Author(s):  
Romaine Ingrid Fernando ◽  
Jay Wimalasena
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Dominant Negative ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

scholarly journals A Novel Human Phosphatidylethanolamine-binding Protein Resists Tumor Necrosis Factor α-induced Apoptosis by Inhibiting Mitogen-activated Protein Kinase Pathway Activation and Phosphatidylethanolamine Externalization

2004 ◽  
Vol 279 (44) ◽  
pp. 45855-45864 ◽  
Author(s):  
Xiaojian Wang ◽  
Nan Li ◽  
Bin Liu ◽  
Hongying Sun ◽  
Taoyong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Induced Apoptosis ◽  
Phosphatidylethanolamine Binding Protein ◽  
Necrosis Factor ◽  
Mcf 7

The phosphatidylethanolamine (PE)-binding proteins (PEBPs) are an evolutionarily conserved family of proteins with pivotal biological functions. Here we describe the cloning and functional characterization of a novel family member, human phosphatidylethanolamine-binding protein 4 (hPEBP4). hPEBP4 is expressed in most human tissues and highly expressed in tumor cells. Its expression in tumor cells is further enhanced upon tumor necrosis factor (TNF) α treatment, whereas hPEBP4 normally co-localizes with lysosomes, TNFα stimulation triggers its transfer to the cell membrane, where it binds to Raf-1 and MEK1. L929 cells overexpressing hPEBP4 are resistant to both TNFα-induced ERK1/2, MEK1, and JNK activation and TNFα-mediated apoptosis. Co-precipitation andin vitroprotein binding assay demonstrated that hPEBP4 interacts with Raf-1 and MEK1. A truncated form of hPEBP4, lacking the PE-binding domain, maintains lysosomal co-localization but has no effect on cellular responses to TNFα. Given that MCF-7 breast cancer cells expressed hPEBP4 at a high level, small interfering RNA was used to silence the expression of hPEBP4. We demonstrated that down-regulation of hPEBP4 expression sensitizes MCF-7 breast cancer cells to TNFα-induced apoptosis. hPEBP4 appears to promote cellular resistance to TNF-induced apoptosis by inhibiting activation of the Raf-1/MEK/ERK pathway, JNK, and PE externalization, and the conserved region of PE-binding domain appears to play a vital role in this biological activity of hPEBP4.

scholarly journals RuvBL1 Maintains Resistance to TRAIL-Induced Apoptosis by Suppressing c-Jun/AP-1 Activity in Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Hao Li ◽  
Taoran Zhou ◽  
Yue Zhang ◽  
Hengyi Jiang ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
The Common ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Necrosis Factor

Lung cancer is the common malignant tumor with the highest death rate in the world. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a potential anticancer agent induces selective apoptotic death of human cancer cells. Unfortunately, approximately half of lung cancer cell lines are intrinsically resistant to TRAIL-induced cell death. In this study, we identified RuvBL1 as a repressor of c-Jun/AP-1 activity, contributing to TRAIL resistance in lung cancer cells. Knocking down RuvBL1 effectively sensitized resistant cells to TRAIL, and overexpression of RuvBL1 inhibited TRAIL-induced apoptosis. Moreover, there was a negative correlation expression between RuvBL1 and c-Jun in lung adenocarcinoma by Oncomine analyses. High expression of RuvBL1 inversely with low c-Jun in lung cancer was associated with a poor overall prognosis. Taken together, our studies broaden the molecular mechanisms of TRAIL resistance and suggest the application of silencing RuvBL1 synergized with TRAIL to be a novel therapeutic strategy in lung cancer treatment.

Thioridazine Enhances TRAIL Cytotoxicity in Human Myeloid Leukemic Cells By up-Regulating DR5 and Modulating PI3K-AKT-NF-Kb Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4938-4938
Author(s):  
Yi Wang ◽  
Yangyi Bao ◽  
Leiming Xia ◽  
Liu Liu ◽  
Kunyuan Guo ◽  
...  
Keyword(s):  
Cancer Research ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Down Regulation ◽  
Trail Receptors ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Necrosis Factor

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells but not in most normal cells, and is identified to be effective in various cancers, include myeloid leukemic cells[1]. Although some leukemia cell lines, K562 and KG-1, are sensitive to TRAIL, many showed certain degrees of resistance to TRAIL-mediated apoptosis[2,3], and the mechanism remains largely unknown, which forced us to find out ways to solve the problem. In this study, we investigated whether thioridazine, a phenothiazine derivative, could overcome the TRAIL resistance in K562 and KG-1 cells. Recently, we showed that Compared to treatment with thioridazine or TRAIL alone, co-treatment with thioridazine and TRAIL-induced apoptosis in K562 and KG-1 cells synergistically. This combination led to activation of caspase-8 and Bid, the cytosolic cumulation of cytochrome c from mitochondria as well as caspase-3 activated downstream. Treatment with thioridazine induced down-regulation of PI3K-AKT-NF-κB pathway. meanwhile, thioridazine dropped the level of NF-κB-dependent Bcl-xL, leading caspase activated and Bid cleaved. the expression of TRAIL-receptors in both K562 and KG-1 cells underwentthe treatment of thioridazine investigated that thioridazine significantly up-regulated DR5 by up to 51.22%, but not other TRAIL-receptors such as DR4, decoy receptor 1, and DcR2. Therefore, our results indicate that the combination of TRAIL with thioridazine overturn TRAIL resistance through Up-regulating the expression of DR5 and down-regulation of AKT protein, and combination treatment with thioridazine and TRAIL may be a novel therapeutic strategy in leukemia. Reference: Srivastava R K. TRAIL/Apo-2L: mechanisms and clinical applications in cancer.[J]. Neoplasia, 2001, 3(6):535-546. Nimmanapalli R, Porosnicu M, Nguyen D, et al. Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells.[J]. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 2001, 7(2):350-357. Yang T, Lan J, Huang Q, et al. Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation.[J]. Cell Biochemistry & Biophysics, 2015, 71(1):291-297. Disclosures No relevant conflicts of interest to declare.

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