RESUMO
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 five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two 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 tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: 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. Clin Cancer Res; 24(12); 2886-900. ©2018 AACR.
Assuntos
Histona Acetiltransferases/metabolismo , Complexos Multiproteicos/metabolismo , Neoplasias/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Antineoplásicos/farmacologia , Caspase 8/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Expressão Gênica , Histona Acetiltransferases/genética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Ligação Proteica , Proteínas de Ligação a RNA/genética , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/genéticaRESUMO
Sex hormones modulate proliferation, apoptosis, migration, metastasis and angiogenesis in cancer cells influencing tumourigenesis from the early hyperplastic growth till the end-stage metastasis. Although decades of studies have detailed these effects at the level of molecular pathways, where and when these actions are needed for the growth and progression of hormone-dependent neoplasia is poorly elucidated. Investigation of the hormone influences in carcinogenesis in the spatio-temporal dimension is expected to unravel critical steps in tumour progression and in the onset of resistance to hormone therapies. Non-invasive in vivo imaging represents a powerful tool to follow in time hormone signalling in the whole body during tumour development. This review summarizes the tools currently available to follow hormone action in living organisms.
