The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells

• Published in: Cell death & disease Vol. 12; no. 9; pp. 816 - 11
• Main Authors: Hannes, Sabine, Karlowitz, Rebekka, van Wijk, Sjoerd J. L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.08.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/95; 631/67; 692/699/67; Amino Acid Chloromethyl Ketones; AMP; Antibodies; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; CRISPR; Cyclic GMP; DIABLO protein; Gene Expression Regulation - drug effects; Humans; Immunology; Immunomodulation; Interferon; Interferon regulatory factor 1; Interferon Regulatory Factor-1 - metabolism; Interferon-beta - metabolism; Kinases; Life Sciences; MAP kinase; Membrane Proteins - metabolism; Necroptosis; Necroptosis - drug effects; NF-kappa B - metabolism; NF-κB protein; Nucleotides, Cyclic; Oligopeptides - pharmacology; Pancreatic cancer; Pancreatic carcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Pheochromocytoma cells; Phosphorylation; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; siRNA; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04014-x

Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.