RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis and necroptosis has been attributed to RIP1/3 complexes. Experimental design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass Spectrometry identified 5 acetylations in the kinase and death domain of RIP1. The novel characterised pan-SirT inhibitor, MC2494, increases RIP1 acetylation at 2 additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumour-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumour-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumour-preventive activity by blocking DMBA-induced mammary gland hyper-proliferation in vivo. Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.

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