Abstract 14774: Rescue of Diabetes-related Impairment of Ischemia-mediated Neovascularization With Fenofibrate Treatment

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kushwin Rajamani ◽  
Jun Yuan ◽  
Laura Lecce ◽  
Alicia Jenkins ◽  
Anthony Keech ◽  
...  
Keyword(s):  
Blood Flow ◽  
Drug Targets ◽  
Capillary Density ◽  
Protective Effects ◽  
Hindlimb Ischemia ◽  
Independent Manner ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Independent Mechanism

Background: Fenofibrate, a PPARα agonist, reduced amputation events in the Fenofibrate Intervention and Event Lowering in Diabetes study among 9795 patients, the mechanisms of which are unknown. We hypothesised that fenofibrate may attenuate diabetes-related impairment in ischemia-mediated neovascularization. Methods: Hindlimb ischemia was induced in a murine model of streptozotocin induced diabetes mellitus (DM) in wildtype and PPARα receptor knockout mice (KO) with/without fenofibrate (30mg/kg/day in high fat diet). Ischemic recovery was assessed by laser doppler, foot movement and capillary density analysis. Key angiogenic events (tubulogenesis) and expression of thioredoxin-interacting protein (TXNIP) mRNA and protein following normal and high glucose (5 vs 25mM glucose) environments were determined in cultured endothelial cells (ECs), with/without selective PPARα receptor antagonist (10μM MK886) and agonist (10μM WY14643). Results: DM profoundly impaired blood flow recovery following hindlimb ischemia (0.51±0.04[n=5] vs 0.34±0.03[n=5];p<0.001). Fenofibrate (FF) restored DM-related impairment in blood flow recovery (0.53±0.04[n=5] vs 0.34±0.03[n=5];p<0.01), capillary density (1.48±0.03 vs1.20±0.04;p<0.01), foot movement scores to levels of non-diabetic controls. Similar findings for fenofibrate were observed in diabetic PPARα KO mice. In vitro, fenofibric acid (FA) rescued hyperglycemia-induced impairment in EC tubulogenesis (87.8 vs 58.3% of control;p<0.05) by a PPARα-independent mechanism. FA prevented hyperglycemia-induced overexpression of TXNIP (mRNA: 1.20±0.16 vs 1.84±0.28 folds of control;p<0.01) an exquisitely glucose-sensitive regulator of angiogenesis, in a PPARα-independent manner. Furthermore, overexpression of TXNIP abrogated the protective effects of FA. Conclusions: Fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis via a largely PPARα-independent mechanism. Improved neovascularization may therefore explain in part the reduced amputations seen with fenofibrate in type 2 diabetes. These findings provide a novel mechanistic understanding for fenofibrate action and may provide a platform for new drug targets.

scholarly journals Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

2021 ◽  
Vol 18 (2) ◽  
pp. 147916412199903
Author(s):  
Laura Croteau ◽  
Clément Mercier ◽  
Étienne Fafard-Couture ◽  
Alexandre Nadeau ◽  
Stéphanie Robillard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Phosphatase Activity ◽  
Capillary Density ◽  
Artery Ligation ◽  
Vegf Signaling ◽  
Post Surgery ◽  
Src Homology ◽  
Artery Disease ◽  
Ischemic Muscle

Aims: Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. Methods: Nondiabetic and diabetic mice, with ( ec-Prkcd−/−) or without ( ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. Results: Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. Conclusions: Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

Abstract 15630: Direct Renin Inhibition With Aliskiren Improves Ischemia-Induced Neovascularization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michel Desjarlais ◽  
Sylvie Dussault ◽  
Wahiba Dhahri ◽  
Alain Rivard
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renin Angiotensin System ◽  
Cellular Migration ◽  
High Dose ◽  
Hindlimb Ischemia ◽  
Adhesive Properties ◽  
Tubule Formation ◽  
Renin Inhibition

Background: The activation of the renin-angiotensin system is associated with impaired formation of new blood vessels (neovascularization) in response to ischemia. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization following ischemia. Methods and Results: C57BL/6 mice were treated with a high dose of aliskiren (50 mg/kg), a low dose of aliskiren (10 mg/kg), or drinking water only. After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Treatment with aliskiren led to a significantly faster rate of blood flow recovery after hindlimb ischemia (Laser Doppler). Interestingly the lower dose of aliskiren, which did not reduce blood pressure, provided similar improvement of blood flow recuperation compared to the higher dose of aliskiren. At day 21 after surgery, Doppler flow ratios were significantly improved in mice treated with aliskiren (0.69+/-0.07 vs. 0.52+/-0.03; p<0.05). This was associated with an increased expression of angiogenic factors in ischemic muscles, including VEGF and eNOS. Endothelial progenitor cells (EPCs) have been shown to have an important role in postnatal neovascularisation. We found that aliskiren significantly increased the number of bone marrow EPCs at day 7 after ischemia (172+/-7% increase; p<0.05). Moreover, the adhesive properties of EPCs were significantly improved in mice treated with aliskiren (175+/-5% increase; p<0.05). In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (DAF staining), and a significant reduction of oxidative stress levels (DHE staining). Importantly, the antioxidant and angiogenic properties of aliskiren in HUVECs are abolished following treatment with the NOS inhibitor L-NAME. Conclusions: Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanisms involve beneficial effects of aliskiren on NO and angiogenic pathways in ischemic tissues, together with an increase in the number and the functional activity of EPCs.

Abstract 663: Angiotensin-(1-7)-MAS Receptor Gene Knockout Impairs Post-ischemic Hindlimb Neovascularization

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jousie M Pereira ◽  
Robson A Santos ◽  
Brigida G Schirmer ◽  
Lucía S Barcelos
Keyword(s):  
Blood Flow ◽  
Perfusion Imaging ◽  
Gene Knockout ◽  
Receptor Gene ◽  
Vascular Density ◽  
Protective Effects ◽  
Hindlimb Ischemia ◽  
Ischemic Limb ◽  
Mas Receptor ◽  
Adductor Muscles

Introduction: Angiotensin-(1-7) is known by its cardiovascular protective effects by activating MAS receptor. It has been shown that Angiotensin-(1-7) stimulates proliferation of endothelial progenitor cells in vitro, but exerts antiangiogenic effects both in inflammatory and tumor environments in vivo. The role of Angiotensin-(1-7)-MAS axis on ischemic conditions was never reported. Hypothesis: We assessed the hypothesis that MAS receptor signaling plays a role in reparative neovascularization after hindlimb ischemia in mice. METHODS: C57BL/6 wild-type (WT) and MAS receptor knockout (MAS-KO) mice (8-10 weeks) were subjected to unilateral permanent left femoral artery occlusion (FAO). Hindlimb blood flow was measured before and immediately after FAO, and 7 and 14 days after FAO by laser Doppler perfusion imaging (LDPI).To further assess the vascularization in the ischemic limb, 28 days after FAO, we used the technique of microbubles contrast enhanced ultrasound perfusion imaging that enables a more sensitive discrimination of blood flow in deep microvessels. Capillary and arteriole density were evaluated by histological analysis at day 14 after FAO. Results: Vascular density was similar in normoperfused muscles from MAS-KO and WT mice. However, the neovascularization response to hindlimb ischemia was significantly reduced in MAS-KO muscles at capillary (p<0.05; n=4/group) and arteriole (p<0.05; n=4/group) level, which led to lesser perfusion recovery of the ischemic limb of MAS-KO mice as evaluated by LDPI (Day 7: 0.67±0.04 vs 0.85±0.04 ischemic/contralateral ratio, p <0.01; Day 14: 0.62±0.15 vs 0.91±0.03, p<0.001; n=8-12/group). In accordance, we observed that MAS-KO mice require shorter time to peak enhancement of microbubles contrast in ischemic adductor muscles compared with WT mice (p<0.01; n = 5-6/group). Conclusion: In conclusion, our data suggests that post-ischemic hindlimb neovascularization and blood flow recovery are impaired in Angiotensin-(1-7)-MAS receptor knockout mice.

Abstract 11: Thioredoxin-Interacting Protein Is Required for VEGF-Induced Angiogenesis Through Regulation of VEGFR2 Internalization

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Shin-Young Park ◽  
Chen Yan ◽  
Bradford C Berk
Keyword(s):  
Umbilical Vein ◽  
Fold Increase ◽  
Tube Formation ◽  
In Vivo Studies ◽  
Vegf Receptor ◽  
Cell Fractionation ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

Introduction— Thioredoxin-interacting protein (TXNIP) is an arrestin-like scaffold protein. We have shown previously that it is necessary for the transactivation of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) as well as promoting the migration and survival of endothelial cells (ECs). However, its roles in VEGF-induced angiogenesis and in vivo studies of TXNIP function have not been elucidated. Hypothesis— TXNIP regulates VEGF-mediated angiogenesis through modulation of angiogenic signaling pathways in ECs. Methods and Results— To determine the functions of TXNIP in ECs, we generated endothelial-specific TXNIP knockout (EC-TXNIP KO) mice (TXNIPflox/flox: Tie2-Cre/+). These mice displayed impaired capillary growth of the retinal vasculature compared to control mice. Furthermore, aortic rings from EC-TXNIP KO mice exhibited fewer and shorter vascular sprouts than those in control mice. To investigate the role of TXNIP in the regulation of VEGF-induced angiogenesis, we determined the subcellular localization of TXNIP in human umbilical vein EC (HUVEC). Immunofluorescence and cell fractionation studies revealed that upon VEGF stimulation (10ng/ml). TXNIP translocated from cytoplasm to the plasma membrane. There was a 9 fold increase of membrane associated TXNIP with a peak at 15 minutes compared to non-VEGF treatment cells. We hypothesized that membrane associated TXNIP may modulate VEGFR2 internalization and thereby affect VEGF-induced signaling and angiogenesis. To investigate this, we performed in vitro cell surface biotinylation assays in HUVEC. VEGFR2 internalization was decreased by 65% in TXNIP siRNA knockdown cells compared to control siRNA treated cells following VEGF stimulation. Consistent with this result, VEGF-induced phosphorylation of VEGFR2, PLCγ and ERK1/2 was decreased by knockdown of TXNIP. Significantly, TXNIP knockdown inhibited VEGF-induced proliferation and tube formation in vitro. Conclusion— Our results suggest that TXNIP can modulate VEGF-induced angiogenesis and signaling by regulation of VEGFR2 internalization.

Abstract 6253: Increased Expression of Thioredoxin Interacting Protein Promotes Oxidative Stress and Contributes to the Pathogenesis Of Diabetic Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kim A Connelly ◽  
Darren J Kelly ◽  
Michael Zhang ◽  
Kerri Thai ◽  
Andrew Advani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
High Glucose ◽  
Diastolic Heart Failure ◽  
Transgenic Rat ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Neonatal Cardiomyocytes

Background: Alterations in the thioredoxin (TRX) antioxidant system have been implicated in the pathogenesis of cardiac injury, particularly in the diabetic setting. While constitutively present, TRX activity is reduced by the presence of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We hypothesized that by increasing TxnIP, diabetes may reduce TRX activity and contribute to oxidative stress. Methods: Cell culture studies were performed using the H9C2 rat cardiomyoblast cell line and neonatal cardiomyocytes isolated from 1 day old Sprague Dawley rat neonates. In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as a measure of oxidative stress. Results: In- vitro, high glucose (25mmol/l) resulted in increased TxnIP mRNA expression in both neonatal cardiomyocytes as well as H92C cells (2.21 ± 0.6 v 1.00 ± 0.19, p<0.05 compared to normoglycaemic conditions) with a 45% reduction in TRX activity (0.11 ± 0.01 v 0.061± 0.003, p<0.01). In-vivo, diabetes led to a 250% rise in TxnIP mRNA expression compared to control (2.54 ± 0.5 v 1.00 ± 0.11, p<0.001) that was accompanied by a three fold rise in urinary 8-OHdG (680 ± 280 v 1395 ± 391 ng/ml, p<0.001). Conclusion: In both the in vitro and in vivo settings, high glucose leads to TxnIP over-expression associated with reduced TRX activity thereby increasing oxidative stress and implicating this system in the pathogenesis of the cardiac dysfunction that characterizes the diabetic state. Pharmacological manipulation of the TRX-TxnIP system may represent a novel target to reduce diabetic complications.

scholarly journals A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis

2013 ◽  
Vol 305 (2) ◽  
pp. E263-E270 ◽  
Author(s):  
Sevasti Zervou ◽  
Tanmoy Ray ◽  
Natasha Sahgal ◽  
Liam Sebag-Montefiore ◽  
Rebecca Cross ◽  
...  
Keyword(s):  
Feedback Inhibition ◽  
Global Gene Expression ◽  
Negative Regulator ◽  
Specific Response ◽  
Mrna Levels ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Creatine Uptake

Creatine is important for energy metabolism, yet excitable cells such as cardiomyocytes do not synthesize creatine and rely on uptake via a specific membrane creatine transporter (CrT; SLC6A8). This process is tightly controlled with downregulation of CrT upon continued exposure to high creatine via mechanisms that are poorly understood. Our aim was to identify candidate endogenous CrT inhibitors. In 3T3 cells overexpressing the CrT, creatine uptake plateaued at 3 h in response to 5 mM creatine but peaked 33% higher ( P < 0.01) in the presence of cycloheximide, suggesting CrT regulation depends on new protein synthesis. Global gene expression analysis identified thioredoxin-interacting protein (Txnip) as the only significantly upregulated gene (by 46%) under these conditions ( P = 0.036), subsequently verified independently at mRNA and protein levels. There was no change in Txnip expression with exposure to 5 mM taurine, confirming a specific response to creatine rather than osmotic stress. Small-interfering RNA against Txnip prevented Txnip upregulation in response to high creatine, maintained normal levels of creatine uptake, and prevented downregulation of CrT mRNA. These findings were relevant to the in vivo heart since creatine-deficient mice showed 39.71% lower levels of Txnip mRNA, whereas mice overexpressing the CrT had 57.6% higher Txnip mRNA levels and 28.7% higher protein expression compared with wild types (mean myocardial creatine concentration 124 and 74 nmol/mg protein, respectively). In conclusion, we have identified Txnip as a novel negative regulator of creatine levels in vitro and in vivo, responsible for mediating substrate feedback inhibition and a potential target for modulating creatine homeostasis.

scholarly journals Vitamin D Prevents High Glucose-Induced Lipid Droplets Accumulation in Cultured Endothelial Cells: The Role of Thioredoxin Interacting Protein

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1874
Author(s):  
Roberta Scrimieri ◽  
Alessandra Cazzaniga ◽  
Sara Castiglioni ◽  
Jeanette A. M. Maier
Keyword(s):  
Vitamin D ◽  
Endothelial Cells ◽  
High Glucose ◽  
Lipid Droplets ◽  
Acid Oxidation ◽  
Protective Effects ◽  
Redox Equilibrium ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Cultured Endothelial Cells

Vitamin D (VitD) exerts protective effects on the endothelium, which is fundamental for vascular integrity, partly by inhibiting free radical formation. We found that VitD prevents high glucose-induced Thioredoxin Interacting Protein (TXNIP) upregulation. Increased amounts of TXNIP are responsible for the accumulation of reactive oxygen species and, as a consequence, of lipid droplets. This is associated with increased amounts of triglycerides as the result of increased lipogenesis and reduced fatty acid oxidation. Remarkably, VitD rebalances the redox equilibrium, restores normal lipid content, and prevents the accumulation of lipid droplets. Our results highlight TXNIP as one of the targets of VitD in high glucose-cultured endothelial cells and shed some light on the protective effect of VitD on the endothelium.

scholarly journals Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3

2021 ◽  
Author(s):  
Yuankun Ma ◽  
Liangliang Jia ◽  
Yidong Wang ◽  
Yongli Ji ◽  
Jian Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Flow ◽  
Heme Oxygenase ◽  
Tissue Damage ◽  
Molecular Mechanisms ◽  
Capillary Density ◽  
Heme Oxygenase 1 ◽  
Inflammasome Activation ◽  
Hindlimb Ischemia ◽  
Antiangiogenic Effect

Objective: Macrophage-mediated inflammatory response is closely associated with the neovascularization process following hindlimb ischemia. We previously demonstrated that HO-1 (heme oxygenase-1) in macrophages evoked proinflammatory reactions and tissue damage. Here, we evaluated the role played by macrophage-derived HO-1 and elucidated its underlying molecular mechanisms in perfusion recovery after hindlimb ischemia. Approach and Results: We found significant upregulation of HO-1 in mouse ischemic muscles after hindlimb ischemia surgery and with most of this expression occurring in infiltrated macrophages. Myeloid conditional HO-1-deficient mice exhibited higher perfusion recovery, evidenced by restored blood flow, motor function and attenuated tissue damage as well as increased capillary density in the gastrocnemius muscles after hindlimb ischemia, relative to littermate controls. This protective effect was accompanied by reduced nod-like receptor family, NLRP3 (pyrin domain containing 3) inflammasome activation in the infiltrated macrophages without the alteration of macrophage infiltration and polarization. Moreover, suppressing inflammasome activation with NLRP3 inhibitor MCC950 improved blood flow and capillary density in wild-type mice compared with untreated mice. Mechanistically, suppressing HO-1 abolished TNF (tumor necrosis factor)-α-induced NLRP3 protein rather than mRNA expression in bone marrow–derived macrophages, indicating that HO-1 mediated post-transcriptional regulation of NLRP3. Furthermore, HO-1 inhibition promoted autolysosome-dependent degradation of NLRP3 in bone marrow–derived macrophages. Matrigel tube formation assay revealed that HO-1 deletion abrogated the antiangiogenic effect of inflammasome-activated macrophages. Conclusions: Taken together, these findings indicate that macrophage HO-1 deficiency promotes perfusion recovery after hindlimb ischemia by accelerating autolysosomal degradation of NLRP3. The underlying mechanism of action is a potential target for therapeutic angiogenesis in ischemic diseases.

scholarly journals Short hairpin RNAs artifactually impair cell growth and suppress clustered microRNA expression

2018 ◽  
Author(s):  
JT Powers ◽  
EL da Rocha ◽  
DS Pearson ◽  
P Missios ◽  
TY de Soysa ◽  
...  
Keyword(s):  
Cancer Research ◽  
Cell Growth ◽  
Drug Targets ◽  
Gene Expression Signature ◽  
Cell Cycle Gene ◽  
Independent Manner ◽  
Short Hairpin ◽  
Independent Effects ◽  
Sirna Knockdown

Functional gene disruption is a central tenet of cancer research, where novel drug targets are often identified and validated through cell-growth based knockdown studies or screens. Short hairpin RNA (shRNA)-mediated mRNA knockdown is widely used in both academic and pharmaceutical settings. However, off-target effects of shRNAs as well as interference with endogenous small RNA processing have been reported. We show here that lentiviral delivery of both gene-specific and non-targeting control shRNAs impair in vitro cell growth in a sequence independent manner. In addition, exogenous shRNAs induce a depressed cell-cycle-gene expression signature that is also shRNA-sequence independent and present across several studies. Further, we observe an shRNA mediated general repression of microRNAs belonging to polycistronic genetic clusters, including microRNAs from established oncogenic microRNA clusters. The collective impact of these observations is particularly relevant for cancer research, given the widespread historical use of shRNAs and the common goal of interrogating genes that regulate proliferation. We therefore recommend that when employing shRNA for target validation, care be taken to titrate shRNA dose, use hairpin-expressing controls, perform gene-of-interest rescue experiments and/or corroborate shRNA-derived results by small interfering RNA (siRNA) knockdown or CRISPR/Cas9-mediated genetic knockout. Minimizing these deleterious sequence independent effects will improve research fidelity and help address reported challenges in experimental reproducibility.

scholarly journals RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

2020 ◽  
Author(s):  
Yiwu Yan ◽  
Bo Zhou ◽  
Chen Qian ◽  
Alex Vasquez ◽  
Avradip Chatterjee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Drug Targets ◽  
Cancer Metastasis ◽  
Therapeutic Interventions ◽  
Interacting Protein ◽  
Prostate Cancer Metastasis ◽  
Prostate Cancers

AbstractDespite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

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