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Abstract
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.
Highlights
Pancreatic cancer (PC) is a devastating disease with a dismal 5-year survival rate of only 9% [1]
2′ 3-cGAMP/BV6/zVAD.fmk-induced cell death could be reduced by Nec-1s-mediated inhibition of RIPK1 in all PC cell lines tested (Fig. 1B), pointing towards RIPK1-dependent necroptotic cell death
Prominent 2′3′-cGAMP/BV6-induced cell death could be detected in caspase-8-deficient PC cell lines, confirming the effects observed with 2′3′-cGAMP/BV6/zVAD.fmk and excluding potential side effects of zVAD.fmk addition (Fig. 1D)
Summary
Pancreatic cancer (PC) is a devastating disease with a dismal 5-year survival rate of only 9% [1]. PC is the fourth leading cause of cancer-related death in the United States and the seventh worldwide [1, 2]; despite continuous efforts to improve PC survival, mortality rates have been rising over the last 4 years [1]. Induction of necroptosis might be a promising strategy to trigger programmed cell death and to overcome treatment resistance in apoptosis-resistant PC cells [5]. Necrosome formation is facilitated by deubiquitination of RIPK1, e.g., upon exposure to second mitochondria-derived activator of caspases (Smac) mimetics, such as BV6, which antagonize cellular inhibitor of apoptosis (cIAP) proteins, which ubiquitinate RIPK1 [9]. The mechanisms of necroptosis induction by the prototypical Smac mimetic BV6 and death receptor agonists, such as tumor necrosis factor-α (TNFα) and TNFα-related apoptosis-inducing ligand, are wellstudied, but alternative necroptotic stimuli have been identified as well [13,14,15]
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