Smac mimetic sensitizes renal cell carcinoma cells to interferon-α-induced apoptosis. Issue 1 (28th May 2016)

• Record Type: Journal Article
• Authors: Reiter, Michael; Eckhardt, Ines; Haferkamp, Axel; Fulda, Simone
• Is Part Of: Cancer letters. Volume 375:Issue 1(2016)
• Page Start: 1
• Page End: 8
• Publication Date: 2016-05-28
• Subjects: Apoptosis -- Smac mimetics -- IAP proteins -- Renal cell carcinoma; AML acute myeloid leukemia -- BIR baculovirus IAP repeat -- cIAP cellular IAP -- FADD Fas-Associated Death Domain protein -- FCS fetal calf serum -- IAP Inhibitor of Apoptosis -- IFNα interferon-α -- IL-2 interleukin-2 -- Nec-1 necrostatin-1 -- PI propidium iodide -- RCC renal cell carcinoma -- RING Really Interesting New Gene -- RIP Receptor-Interacting Protein -- RNAi RNA interference -- shRNA short-hairpin RNA -- Smac second mitochondria-derived activator of caspase -- TNF Tumor Necrosis Factor -- TNFR TNF receptor -- TRAIL TNF-related apoptosis-inducing ligand -- XIAP X-linked IAP -- zVAD.fmk N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.02.019
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Smac mimetic and IFNα cooperate to induce apoptosis in renal cell carcinoma cells. RIP1 protein is required for Smac mimetic/IFNα-mediated apoptosis. Smac mimetic/IFNα-mediated apoptosis occurs independently of TNFα. Abstract: The prognosis of metastatic or relapsed renal cell carcinoma (RCC) is still very poor, highlighting the need for new treatment strategies. Here, we identify a cooperative antitumor activity of interferon-α (IFNα) together with the Smac mimetic BV6 that antagonizes antiapoptotic IAP proteins. BV6 and IFNα act together to reduce cell viability and to induce apoptosis in various RCC cell lines. Molecular studies revealed that BV6/IFNα co-treatment triggers apoptosis independently of autocrine/paracrine Tumor Necrosis Factor (TNF)α signaling, since the TNFα-blocking antibody Enbrel fails to rescue cell death. Importantly, knockdown of Receptor-Interacting Protein (RIP)1 significantly decreases BV6/IFNα-mediated apoptosis, whereas the RIP1 kinase inhibitor necrostatin-1 (Nec-1) provides no protection. This demonstrates that RIP1 protein is critically required for BV6/IFNα-induced apoptosis, while RIP1 kinase activity is dispensable, pointing to a scaffold function of RIP1. Consistently, BV6 and IFNα cooperate to trigger the interaction of RIP1, Fas-Associated Death Domain protein (FADD) and caspase-8 to form a cytosolic cell death complex that drives caspase activation. Addition of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly protects RCC cells against BV6/IFNα-induced apoptosis, demonstrating that caspase activity is required for apoptosis. In conclusion, the combination approach of IFNα and BV6 represents a promising strategy for cooperative induction of apoptosis in RCC cells, which warrants further investigation.