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Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells

We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca al...

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Autores principales: Czaplinski, Sebastian, Abhari, Behnaz Ahangarian, Torkov, Alica, SeggewiΔ, Dominik, Hugle, Manuela, Fulda, Simone
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747171/
https://www.ncbi.nlm.nih.gov/pubmed/26575016
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author Czaplinski, Sebastian
Abhari, Behnaz Ahangarian
Torkov, Alica
SeggewiΔ, Dominik
Hugle, Manuela
Fulda, Simone
author_facet Czaplinski, Sebastian
Abhari, Behnaz Ahangarian
Torkov, Alica
SeggewiΔ, Dominik
Hugle, Manuela
Fulda, Simone
author_sort Czaplinski, Sebastian
collection PubMed
description We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB.
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spelling pubmed-47471712016-03-25 Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells Czaplinski, Sebastian Abhari, Behnaz Ahangarian Torkov, Alica SeggewiΔ, Dominik Hugle, Manuela Fulda, Simone Oncotarget Research paper: Autophagy and Cell Death We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB. Impact Journals LLC 2015-11-12 /pmc/articles/PMC4747171/ /pubmed/26575016 Text en Copyright: © 2015 Czaplinski et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research paper: Autophagy and Cell Death
Czaplinski, Sebastian
Abhari, Behnaz Ahangarian
Torkov, Alica
SeggewiΔ, Dominik
Hugle, Manuela
Fulda, Simone
Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title_full Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title_fullStr Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title_full_unstemmed Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title_short Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells
title_sort differential role of rip1 in smac mimetic-mediated chemosensitization of neuroblastoma cells
topic Research paper: Autophagy and Cell Death
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747171/
https://www.ncbi.nlm.nih.gov/pubmed/26575016
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