Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization

Cingöz, Ahmet; Ozyerli-Goknar, Ezgi; Morova, Tunç; Seker-Polat, Fidan; Selvan, Myvizhi Esai; Gümüş, Zeynep H.; Bhere, Deepak; Shah, Khalid; Solaroğlu, İhsan; Bagcı-Önder, Tugba

doi:10.1038/s41388-021-01697-6

Cited by 6 publications

(6 citation statements)

References 72 publications

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“…Interestingly, Bcl-2 overexpression largely suppressed the final cleavage in caspase-8 and also caspase-3; on the other hand, XIAP knockdown led to the improvement of the cellular levels of cleaved caspase-3 upon treatment with TRAIL ( 39 ). Cingöz and his coworkers showed that TRAIL-mediated apoptosis in glioblastoma (GBM) cell lines can be promoted following combination therapy with proteasome inhibitor bortezomib and TRAIL, evidently by down-regulating Bcl-2 or Bcl-xL, suggesting a role for these anti-apoptotic proteins in inducing resistance to apoptosis-inducing cytokines, in particular, TRAIL ( 40 ). Moreover, analysis of the apoptosis process induced by TRAIL in human colon cancer cell line SW620 revealed that although caspase-8 activation and subsequent tBid formation was triggered in tumor cells upon treatment with TRAIL, up-regulating Bcl-2, Bcl-xL and Mcl-1 blocked TRAIL-mediated apoptosis in treated tumor cells ( 41 ).…”

Section: Mechanisms Of Cancer Resistances To Trailmentioning

confidence: 99%

“…Interestingly, co-stimulation with TRAIL and lipopolysaccharides (LPS) more obviously promoted the variations in TRAIL-receptor-expression sponsoring apoptosis resistance due to the recognized effects of LPS on TLR-4 activation ( 52 ). On the other hand, CRISPR/Cas9 mediated silencing of DR5 suppressed bortezomib-mediated re-sensitization of glioblastoma cell lines to TRAIL-induced apoptosis, representing its significant role in determining cell response to TRAIL ( 40 ). Furthermore, it has been suggested that DCR2 could shape a heteromeric complex with the DR5 and consequently diminish caspase-8 activation and apoptosis in human cervical cancer HeLa cells.…”

Section: Mechanisms Of Cancer Resistances To Trailmentioning

confidence: 99%

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RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.

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Section: Mechanisms Of Cancer Resistances To Trailmentioning

confidence: 99%

Section: Mechanisms Of Cancer Resistances To Trailmentioning

confidence: 99%

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

et al. 2021

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“…Alternatively, inhibition of MOMP can occur through overexpression of the anti-apoptotic Bcl-2 family proteins, which inhibit the activity of apoptotic proteins, such as Bax and Bak. Overexpression of anti-apoptotic proteins, such as Bcl-2 or Bcl-XL, reduces apoptosis induced by both granule-mediated cytotoxicity and death receptor-mediated cytotoxicity, whereas pharmacological inhibition of Bcl-2 sensitises cells to cytotoxicity ( 196 , 197 , 202 – 206 ). Overexpression of Bcl-2 is a common feature of multiple cancers ( 207 ).…”

Section: Mechanisms Of Resistance To Cytotoxicitymentioning

confidence: 99%

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

2022

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Cytotoxic lymphocytes are critical in our immune defence against cancer and infection. Cytotoxic T lymphocytes and Natural Killer cells can directly lyse malignant or infected cells in at least two ways: granule-mediated cytotoxicity, involving perforin and granzyme B, or death receptor-mediated cytotoxicity, involving the death receptor ligands, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). In either case, a multi-step pathway is triggered to facilitate lysis, relying on active pro-death processes and signalling within the target cell. Because of this reliance on an active response from the target cell, each mechanism of cell-mediated killing can be manipulated by malignant and infected cells to evade cytolytic death. Here, we review the mechanisms of cell-mediated cytotoxicity and examine how cells may evade these cytolytic processes. This includes resistance to perforin through degradation or reduced pore formation, resistance to granzyme B through inhibition or autophagy, and resistance to death receptors through inhibition of downstream signalling or changes in protein expression. We also consider the importance of tumour necrosis factor (TNF)-induced cytotoxicity and resistance mechanisms against this pathway. Altogether, it is clear that target cells are not passive bystanders to cell-mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing. Understanding these processes of immune evasion may lead to novel ideas for medical intervention.

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“…Moreover, NF-κB-regulated microRNAs stimulated resistance to TRAIL [95] . CXCL1, a target for NF-κB, stimulated immune cell infiltration via paracrine signaling, leading to TRAIL resistance in PDAC [96] . Based on these results, it can be concluded that NF-κB may influence cellular behavior via various signaling pathways, which should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells

De Wilt,

Sobocki,

Jansen

et al. 2024

Cancer Drug Resist

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Aim: The therapeutic targeting of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors in cancer, including non-small cell lung cancer (NSCLC), is a widely studied approach for tumor selective apoptotic cell death therapy. However, apoptosis resistance is often encountered. The main aim of this study was to investigate the apoptotic mechanism underlying TRAIL sensitivity in three bortezomib (BTZ)-resistant NSCLC variants, combining induction of both the intrinsic and extrinsic pathways. Methods: Sensitivity to TRAIL in BTZ-resistant variants was determined using a tetrazolium (MTT) and a clonogenic assay. A RT-qPCR profiling mRNA array was used to determine apoptosis pathway-specific gene expression. The expression of these proteins was determined through ELISA assays and western Blotting, while apoptosis (sub-G1) and cytokine expression were determined using flow cytometry. Apoptotic genes were silenced by specific siRNAs. Lipid rafts were isolated with fractional ultracentrifugation. Results: A549BTZR (BTZ-resistant) cells were sensitive to TRAIL in contrast to parental A549 cells, which are resistant to TRAIL. TRAIL-sensitive H460 cells remained equally sensitive for TRAIL as H460BTZR. In A549BTZR cells, we identified an increased mRNA expression of TNFRSF11B [osteoprotegerin (OPG)] and caspase-1, -4 and -5 mRNAs involved in cytokine activation and immunogenic cell death. Although the OPG, interleukin-6 (IL-6), and interleukin-8 (IL-8) protein levels were markedly enhanced (122-, 103-, and 11-fold, respectively) in the A549BTZR cells, this was not sufficient to trigger TRAIL-induced apoptosis in the parental A549 cells. Regarding the extrinsic apoptotic pathway, the A549BTZR cells showed TRAIL-R1-dependent TRAIL sensitivity. The shift of TRAIL-R1 from non-lipid into lipid rafts enhanced TRAIL-induced apoptosis. In the intrinsic apoptotic pathway, a strong increase in the mRNA and protein levels of the anti-apoptotic myeloid leukemia cell differentiation protein (Mcl-1) and B-cell leukemia/lymphoma 2 (Bcl-2) was found, whereas the B-cell lymphoma-extra large (Bcl-xL) expression was reduced. However, the stable overexpression of Bcl-xL in the A549BTZR cells did not reverse the TRAIL sensitivity in the A549BTZR cells, but silencing of the BH3 Interacting Domain Death Agonist (BID) protein demonstrated the importance of the intrinsic apoptotic pathway, regardless of Bcl-xL. Conclusion: In summary, increased sensitivity to TRAIL-R1 seems predominantly related to the relocalization into lipid rafts and increased extrinsic and intrinsic apoptotic pathways.

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Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization

Cited by 6 publications

References 72 publications

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

RETRACTED: Harnessing TRAIL-Induced Apoptosis Pathway for Cancer Immunotherapy and Associated Challenges

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells

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