scholarly journals IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer

2018 ◽  
Vol 25 (3) ◽  
pp. 295-308 ◽  
Author(s):  
Thomas A Werner ◽  
Inga Nolten ◽  
Levent Dizdar ◽  
Jasmin C Riemer ◽  
Sina C Schütte ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tissue Microarrays ◽  
Decoy Receptors ◽  
Smac Mimetics ◽  
Long Term Prognosis ◽  
Induced Apoptosis ◽  
Specific Degradation ◽  
Trail System

Follicular thyroid cancer’s (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro. Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144–1.826; P < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2797-2805 ◽  
Author(s):  
Feng-Ting Liu ◽  
Samir G. Agrawal ◽  
John G. Gribben ◽  
Hongtao Ye ◽  
Ming-Qing Du ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Resistant Cell ◽  
Protein Levels ◽  
Bax Protein ◽  
Degradation Activity ◽  
Potent Drug ◽  
Induced Apoptosis

Proapoptotic Bcl-2 family member Bax is a crucial protein in the induction of apoptosis, and its activation is required for this process. Here we report that Bax is a short-lived protein in malignant B cells and Bax protein levels decreased rapidly when protein synthesis was blocked. Malignant B cells were relatively resistant to tumor necrosis factor–related apoptosis inducing ligand (TRAIL)–induced apoptosis, and this correlated with low basal Bax protein levels. Furthermore, during treatment with TRAIL, the resistant cell lines showed prominent Bax degradation activity. This degradation activity was localized to mitochondrial Bax and could be prevented by truncated Bid, a BH3-only protein; in contrast, cytosolic Bax was relatively stable. The proteasome inhibitor bortezomib is a potent drug in inducing apoptosis in vitro in malignant B-cell lines and primary chronic lymphocytic leukemic (CLL) cells. In CLL cells, bortezomib induced Bax accumulation, translocation to mitochondria, conformational change, and oligomerization. Accumulation and stabilization of Bax protein by bortezomib-sensitized malignant B cells to TRAIL-induced apoptosis. This study reveals that Bax instability confers resistance to TRAIL, which can be reversed by Bax stabilization with a proteasome inhibitor.

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

2008 ◽  
Vol 294 (3) ◽  
pp. E540-E550 ◽  
Author(s):  
Elida Lai ◽  
George Bikopoulos ◽  
Michael B. Wheeler ◽  
Maria Rozakis-Adcock ◽  
Allen Volchuk
Keyword(s):  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Human Islets ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Relative Contribution ◽  
Induced Apoptosis

Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic β-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced β-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in β-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.

scholarly journals Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis

2004 ◽  
Vol 24 (16) ◽  
pp. 7003-7014 ◽  
Author(s):  
John C. Wilkinson ◽  
Enrique Cepero ◽  
Lawrence H. Boise ◽  
Colin S. Duckett
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Death Receptor ◽  
Full Length ◽  
Proliferative Capacity ◽  
Term Survival ◽  
Truncation Mutant ◽  
Short And Long Term ◽  
Induced Apoptosis

ABSTRACT X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of cell death that functions by suppressing caspases 3, 7, and 9. Here we describe the establishment of Jurkat-derived cell lines stably overexpressing either full-length XIAP or a truncation mutant of XIAP that can only inhibit caspase 9. Characterization of these cell lines revealed that following CD95 activation full-length XIAP supported both short- and long-term survival as well as proliferative capacity, in contrast to the truncation mutant but similar to Bcl-xL. Full-length XIAP was also able to inhibit CD95-mediated caspase 3 processing and activation, the mitochondrial release of cytochrome c and Smac/DIABLO, and the loss of mitochondrial membrane potential, whereas the XIAP truncation mutant failed to prevent any of these cell death events. Finally, suppression of XIAP levels by RNA interference sensitized Bcl-xL-overexpressing cells to death receptor-induced apoptosis. These data demonstrate for the first time that full-length XIAP inhibits caspase activation required for mitochondrial amplification of death receptor signals and that, by acting upstream of mitochondrial activation, XIAP supports the long-term proliferative capacity of cells following CD95 stimulation.

Hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro

2001 ◽  
Author(s):  
Mohammad Islam ◽  
Norio Mitsuhashi ◽  
Tetsuo Akimoto ◽  
Hideyuki Sakurai ◽  
Masatoshi Hasegawa ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Yolk Sac ◽  
Yolk Sac Tumor ◽  
Tumor Cell Lines ◽  
Induced Apoptosis

scholarly journals The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy

2019 ◽  
Vol 20 (6) ◽  
pp. 1306 ◽  
Author(s):  
Mario Scheurer ◽  
Roman Brands ◽  
Mohamed El-Mesery ◽  
Stefan Hartmann ◽  
Urs Müller-Richter ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cell Lines ◽  
In Vitro Study ◽  
Keratinocyte Cell Line Hacat ◽  
Keratinocyte Cell ◽  
Nfκb Pathway ◽  
Induced Apoptosis ◽  
Selection Of ◽  
Hnscc Cell

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors—Cortisol, MLN4924, QNZ and TPCA1—on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.

scholarly journals Hedgehog pathway permissive conditions allow generation of immortal cell lines from granule cells derived from cancerous and non-cancerous cerebellum

Open Biology ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 180145 ◽  
Author(s):  
Constantin Heil
Keyword(s):  
Cell Lines ◽  
Hedgehog Pathway ◽  
Simple Method ◽  
Genetic Ablation ◽  
Neural Lineage ◽  
Shh Pathway ◽  
Pathway Activation

Cerebellar granule cell progenitors (GCPs) undergo proliferation in the post-natal cerebellum that is dependent on sonic hedgehog (SHH) signalling. Deregulated SHH signalling leads to type 2 medulloblastoma (MB). In this work, a novel cell culture protocol is described, which is suitable for the establishment and long-term maintenance of GCP-derived cells. This method is first applied to SHH pathway active MB cells from Atoh1 -cre; Ptch1 FL/FL tumours, which leads to the generation of neurosphere-like cell lines expressing GCP markers and an active SHH signalling pathway. These cells also show high sensitivity to the Smoothened inhibitor vismodegib, therefore recapitulating the SHH pathway requirement for survival shown by type 2 MB. Analysis of culture supplements reveals that bFGF and fetal bovine serum act as inhibitors of the SHH pathway and therefore preclude generation of cell lines that are relevant to the study of the SHH pathway. Consequently, these insights are transferred from the context of MB to non-transformed, post-natal day 7 cerebellum-derived cellular explants. In contrast to other, previously used methods, these GCP cultures proliferate indefinitely and depend on SHH pathway activation, either by means of the small molecule SAG or through genetic ablation of Ptch1 . This culture method therefore leads to the generation of immortal neurosphere-like cell lines, that are named murine SAG-dependent spheres (mSS). Despite long-term culture, mSS cells remain dependent on continuous stimulation of the SHH pathway. Further, mSS cells maintain their lineage after extensive periods in vitro, as demonstrated by their differentiation towards the neural lineage. Herein a simple method for the generation of immortal cell lines from murine cerebella is defined. These lines can be maintained indefinitely through hedgehog pathway activation and maintain the GCP lineage.

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