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Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines
Michael John Cekay1, Stefanie Roesler1, Tanja Frank1
1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528 Frankfurt, Germany.
Abstract:
Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNγ-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNγ-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNγ-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNγ-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNγ to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer.
Insights
Cancer cells can resist apoptosis. This study shows Smac mimetics combined with interferon-gamma (IFNγ) can induce necroptosis, a programmed cell death, in these resistant cancer cells, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Cell Death Pathways
- Immunotherapy
Background:
- Cancer cells frequently evade apoptosis, necessitating alternative cell death induction strategies.
- Necroptosis, a programmed form of necrosis, is a promising therapeutic target for apoptosis-resistant cancers.
- Smac mimetics are a class of drugs that antagonize inhibitors of apoptosis proteins.
Purpose of the Study:
- To investigate the synergistic interaction of Smac mimetics with interferon-gamma (IFNγ) to induce necroptosis in apoptosis-resistant cancer cells.
- To elucidate the molecular mechanisms underlying this synergistic cell death induction.
- To assess the therapeutic potential of this combination strategy in various cancer types.
Main Methods:
- Utilized Smac mimetics (e.g., BV6, Birinapant) and IFNγ in apoptosis-resistant cancer cell lines (solid and hematological).
- Assessed cell death induction and synergism using combination index (CI) calculations.
- Investigated the role of key necroptosis signaling components (RIP1, RIP3, MLKL) and IFN-regulatory factor 1 (IRF1) via genetic knockdown and pharmacological inhibition.
- Differentiated the mechanism from death receptor-mediated pathways by blocking TNFα, TRAIL, and CD95 ligand.
Main Results:
- A novel synergistic interaction between Smac mimetics and IFNγ was identified, inducing necroptosis in apoptosis-resistant cancer cells.
- This synergism was confirmed across diverse cancer cell lines and with different Smac mimetics.
- Genetic and pharmacological inhibition of RIP1, RIP3, or MLKL significantly protected cells from Smac mimetic/IFNγ-induced death, confirming necroptosis involvement.
- IRF1 was found to be essential for this necroptosis induction.
- The observed cell death was independent of canonical death receptor ligands (TNFα, TRAIL, CD95L).
Conclusions:
- Smac mimetics synergize with IFNγ to effectively trigger necroptosis in cancer cells resistant to apoptosis.
- This combination therapy represents a promising strategy for overcoming therapeutic resistance in cancer treatment.
- The findings highlight the potential of targeting necroptosis pathways for novel anti-cancer interventions.
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