ABSTRACT
Opioids are potent drugs that are widely used to control wound or cancer pain. Increasing evidence suggest that opioids mediate clinically relevant effects that go beyond their classical role as analgesics. Of note, opioids appear to modulate angiogenesis - a process that is critical in wound healing and cancer progression. In this review, we focus on pro- and anti-angiogenic facets of opioids that arise from the activation of individual opioid receptors and the usage of individual concentrations or application routes. We overview the still incompletely elucidated mechanisms of these angiogenic opioid actions. Moreover, we describe plausible opioids effects, which - although not primarily studied in the context of vessel formation - may be related to the opioid-driven processes of angiogenesis. Finally we discuss the use of opioids as an innovative therapeutic avenue for the treatment of chronic wounds and cancer.
Subject(s)
Analgesics, Opioid/metabolism , Analgesics, Opioid/pharmacology , Neoplasms/metabolism , Neoplasms/pathology , Neovascularization, Pathologic/metabolism , Neovascularization, Physiologic/drug effects , Wound Healing/drug effects , Animals , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Regulation/drug effects , Humans , Neoplasms/drug therapy , Neoplasms/etiology , Signal Transduction/drug effectsABSTRACT
STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo compared to Stat1-/- NK cells in the absence of detectable transcriptional activity. We thus investigated the STAT1 interactome using primary NK cells derived from Stat1ind mice that inducibly express a FLAG-tagged STAT1. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. In line, immunofluorescence studies uncovered the recruitment of STAT1 to the target-cell interphase during NK cell killing. This led us to propose a novel function for STAT1 at the immunological synapse in NK cells regulating tumor surveillance and cytotoxicity.
