ABSTRACT
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 as a key component of the antioxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the antioxidant master regulator NRF2: Activation of NUAK1 coordinates PP1ß inhibition with AKT activation in order to suppress GSK3ß-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632-47. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
Subject(s)
Colorectal Neoplasms/metabolism , Oxidative Stress , Protein Kinases/metabolism , Repressor Proteins/metabolism , Animals , Binding Sites , Biomarkers , Colonic Polyps/genetics , Colonic Polyps/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease Models, Animal , Disease Progression , Gene Expression , Gene Expression Regulation, Neoplastic , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Lymph Nodes/pathology , Mice , Models, Biological , NF-E2-Related Factor 2/metabolism , Nucleotide Motifs , Prognosis , Protein Binding , Protein Kinases/genetics , Protein Transport , Reactive Oxygen Species/metabolism , Repressor Proteins/geneticsABSTRACT
OBJECTIVE: In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil. METHODS: We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia. RESULTS: We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity. CONCLUSIONS: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction.
Subject(s)
Behavior, Animal/drug effects , Benzhydryl Compounds/therapeutic use , Brain/physiopathology , Central Nervous System Stimulants/therapeutic use , Cognition/drug effects , Hallucinogens/toxicity , Neural Pathways/physiopathology , Phencyclidine/toxicity , Animals , Autoradiography , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Male , Modafinil , Neural Pathways/drug effects , Neural Pathways/metabolism , RatsABSTRACT
BACKGROUND: Cognitive deficits are a core feature of schizophrenia that respond minimally to existing drugs. PCP is commonly used to model schizophrenia-like deficits preclinically although different dosing protocols may affect different domains. Here we characterise the acute, and chronic intermittent effects of PCP in the 5-choice serial reaction time task (5-CSRTT) in rats, and assess the effects of clozapine. In a novel approach, we also assess the effects of increased inhibitory load and conduct clinically relevant signal detection analysis (SDA). MATERIALS AND METHODS: The effects of acute and repeated PCP (2.58 mg/kg) treatment on attentional processes and inhibitory control were assessed during and following the chronic treatment regime in the presence or absence of chronic clozapine (20 mg/kg/day). RESULTS: Thirty minutes post-PCP injection, there was an increase in anticipatory responding which disappeared after 24 h. Although, acute PCP did not change accuracy of responding or processing speed, repeated PCP revealed delayed deficits in cognitive processing speed which were partly ameliorated by clozapine. Extended inter-trial intervals increased premature responding, while SDA revealed that clozapine modified persistent PCP-induced deficits in lnBeta (a composite measure of risk taking versus caution). CONCLUSION: Acute NMDA receptor antagonism impairs inhibitory control, whereas repeated treatment produces delayed deficits in cognitive processing speed. The ability of clozapine partially to restore persistent PCP-induced deficits in processing speed and in lnBeta is consistent with clinical findings. This suggests that the enduring effects of repeated PCP treatment, combined with SDA, offers a useful, translational, approach to evaluate novel cognitive enhancers in the 5-CSRTT.
Subject(s)
Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Cognition Disorders/drug therapy , Phencyclidine/toxicity , Animals , Antipsychotic Agents/administration & dosage , Attention/drug effects , Choice Behavior/drug effects , Clozapine/administration & dosage , Cognition Disorders/chemically induced , Disease Models, Animal , Drug Administration Schedule , GABA Antagonists/administration & dosage , GABA Antagonists/pharmacology , Male , Phencyclidine/administration & dosage , Rats , Rats, Long-Evans , Reaction Time/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Detection, Psychological , Time FactorsABSTRACT
Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT(7) antagonists and M(4) agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.