RESUMEN
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
Asunto(s)
Muerte Celular Inmunogénica , Proteolisis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Transducción de Señal , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Humanos , Animales , Ratones , Proteolisis/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de los fármacos , Necroptosis/efectos de los fármacos , Necroptosis/inmunología , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Ratones Endogámicos C57BL , Antineoplásicos/farmacología , Inmunoterapia/métodosRESUMEN
Folate receptor alpha (FRalpha), a glycosyl phosphatidylinositol linked protein with a great affinity for folic acid and some reduced folates such as 5-methyltetrahydrofolate and tetrahydrofolate is present on a limited number of epithelial cells, especially the kidney, placenta and choroid plexus. It is also over-expressed in many carcinomas. The receptor appears to remain membrane bound but cycles between the cell surface and an internal compartment. Its localization to detergent resistant membranes (lipid rafts) may be important to its cycling and indeed putative function to conserve folate in selected body compartments. Agents that disrupt the actin cytoskeleton such as cytochalasin D as well as phorbol myristic acid effect cycling of the receptor. The monkey kidney cell line, MA104, has proved to be a useful model for studying FRalpha cycling and 5-methyltetrahydrofolate accumulation. This chapter reviews much of this work and compares and contrasts it to studies of other cells, both normal and malignant.