RAF Inhibition Overcomes Resistance to TRAIL-Induced Apoptosis in Melanoma Cells

Berger, Anja; Quast, Sandra-Annika; Plötz, Michael; Kuhn, Nicholas-Frederik; Trefzer, Uwe; Eberle, Jürgen

doi:10.1038/jid.2013.347

Cited by 34 publications

(42 citation statements)

References 59 publications

(82 reference statements)

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“…Bim and Puma) (Willis and Adams, 2005). Decisive roles of Bcl-2 and Bax for death ligand sensitivity of melanoma cells were shown by Bcl-2 overexpression, which prevented sensitivity Raisova et al, 2001), and by Bax activation through different inhibitors, which enhanced TRAIL sensitivity Berger et al, 2014;Quast et al, 2012;Quast et al, 2013). Also in the present setting, Bcl-2 and Bay played decisive roles.…”

Section: Discussionmentioning

confidence: 51%

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Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

Quast

Steinhorst

Plötz

et al. 2015

Journal of Investigative Dermatology

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The death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) represents a promising strategy for melanoma due to significant expression of TRAIL receptor 1 in melanoma metastases and high TRAIL sensitivity through this receptor. However, prevalent and inducible resistance are limiting its clinical use. In previous work, we and others have described multiple strategies leading to TRAIL sensitization; however, the common principles of these strategies remained elusive. Here, we demonstrate in melanoma cell lines (TRAIL-sensitive, TRAIL-resistant, and TRAIL-selected cells with acquired resistance) that cell cycle arrest clearly correlates with enhanced TRAIL sensitivity. Cell cycle arrest was induced by high cell confluence, serum starvation, or cyclin-dependent kinase (CDK) 4/6 inhibition. Addressing the signaling pathways revealed disruption of mitochondrial membrane potential and production of reactive oxygen species (ROS) in response to antiproliferative conditions alone. Activation of the proapoptotic Bcl-2 protein Bax and inhibition of apoptosis by Bcl-2 overexpression or by the antioxidant N-acetyl cysteine underlined the critical involvement of mitochondrial apoptosis pathways and of ROS, respectively. Most pronounced was the upregulation of small proapoptotic Bcl-2 proteins (Puma and Bcl-xS). These data provide a general understanding on TRAIL sensitization as well as an alternative view on CDK inhibitors and may suggest selective targeting of melanoma cells by cell cycle inhibition and TRAIL.

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Section: Discussionmentioning

confidence: 51%

“…inhibition of ion channels or BRAF resulted in G1 arrest (Quast et al, 2012;Berger et al, 2014), whereas an I-κB kinase inhibitor and the natural compound indirubin resulted in G2 arrest (Berger et al, 2011;. Cell cycle arrest therefore appears as the common end path of the different strategies leading to TRAIL sensitization.…”

Section: Discussionmentioning

confidence: 99%

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

Quast

Steinhorst

Plötz

et al. 2015

Journal of Investigative Dermatology

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“…In addition, beneficial alterations in the ratios of pro-apoptotic proteins, Bax and Bak, protein expressions and the anti-apoptotic proteins, Bcl-xL, Mcl-1 and cFLIP, favors overcoming the resistance to TRAIL. 45, 46 Finally, elevations in all three isoforms of Bim contribute to a higher apoptotic response. 47, 48 …”

Section: Discussionmentioning

confidence: 99%

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

et al. 2014

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Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.

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“…21,34 In this study, the combination hvTRA and the clinically used BRAF inhibitor, vemurafenib, was examined. The effect of vemurafenib alone was established in selected cell lines.…”

Section: Resultsmentioning

confidence: 99%

hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma

Fleten

Flørenes

Prasmickaite

et al. 2016

Cell Death Discovery

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In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.

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RAF Inhibition Overcomes Resistance to TRAIL-Induced Apoptosis in Melanoma Cells

Cited by 34 publications

References 59 publications

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma

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