Research Papers: Autophagy and Cell Death:

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

Sebastian Czaplinski, Behnaz Ahangarian Abhari, Alica Torkov, Dominik Seggewiß, Manuela Hugle and Simone Fulda _

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Oncotarget. 2015; 6:41522-41534. https://doi.org/10.18632/oncotarget.6308

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Sebastian Czaplinski1, Behnaz Ahangarian Abhari1, Alica Torkov1, Dominik Seggewiß1, Manuela Hugle1 and Simone Fulda1,2,3

1 Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

2 German Cancer Consortium (DKTK), Heidelberg, Germany

3 German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Simone Fulda, email:

Keywords: Smac mimetic, apoptosis, RIP1, BCL-2 proteins, neuroblastoma

Received: August 07, 2015 Accepted: October 28, 2015 Published: November 12, 2015


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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