Combined chemoradiotherapy and PARP inhibition in pancreatic cancer to induce a synchronous inflammatory cytokine response.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 29-29
Author(s):  
Eric Anderson ◽  
Zhenqiu Liu ◽  
Paul Noe ◽  
Yuzu Kubota ◽  
Wensha Yang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Pancreas Cancer ◽  
Parp Inhibitor ◽  
Locally Advanced ◽  
Parp Inhibition ◽  
Cytokine Signaling ◽  
Combined Chemoradiotherapy ◽  
The Impact

29 Background: Outcomes remain poor for patients with locally advanced pancreas cancer despite advances in combined modality therapy. Radiation and chemotherapy remain the mainstay of treatment for unresectable locally advanced pancreas cancer, and the addition of various agents is currently being assessed in clinical trials. There is increasing evidence that local inflammation and host immune response play a role in anti-tumor activity. We aimed to assess the impact of combined chemoradiotherapy and PARP inhibition on inflammatory cytokine production in pancreas cancer patients. Methods: A clinical trial of concurrent use of a PARP inhibitor with chemoradiation was performed on a cohort of 34 patients. Serum samples were collected at baseline and weekly during intensity modulated radiotherapy treatment. Concentrations of various inflammatory cytokines were measured in picograms per milliliter using a chemiluminescent assay. Comparisons between average percentage change from baseline to peak change of serum cytokine concentration across all patients was performed using a paired T test. Results: Multiple inflammatory cytokines experienced a statistically significant increase after patient treatment. Peak serum increase occurred within 3-5 weeks after treatment initiation for the majority of cytokines tested. The most significantly increased pro-angiogenic cytokines included placental growth factor (p = 2.21x10-6) and vascular endothelial growth factor (p = 1.19x10-4), which peaked at weeks 4 and 5, respectively. Multiple members of the interleukin family also increased significantly. Both IL-7 (p = 1.89x10-4) and IL-17a (p = 7.26x10-4) peaked at weeks 4. IL-5 (p = 8.84x10-5) and IL-15 (p = 1.26x10-15) peaked at weeks 3 and 4, respectively. Conclusions: Patients receiving combined PARP inhibitor and chemoradiation experience a stereotyped increase in inflammatory cytokine signaling that peaks at approximately 1 month after initiation of treatment. Changes in serum inflammatory cytokines may serve as biomarkers of response to treatment and could underpin future combined treatment modalities including immunomodulating agents.

scholarly journals The true cost of in-patient obesity: impact of obesity on inflammatory stress and morbidity

2010 ◽  
Vol 69 (4) ◽  
pp. 511-517 ◽  
Author(s):  
Robert F. Grimble
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
The Body ◽  
Morbidity And Mortality ◽  
Metabolic Effects ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Stress ◽  
Wide Range ◽  
The Impact

The objective of the present review is to provide an overview of the metabolic effects of pro-inflammatory cytokine production during infection and injury; to highlight the disadvantages of pro-inflammatory cytokine production and inflammatory stress on morbidity and mortality of patients; to identify the influence of genetics and adiposity on inflammatory stress in patients and to indicate how nutrients may modulate the inflammatory response in patients. Recent research has shown clearly that adipose tissue actively secretes a wide range of pro- and anti-inflammatory cytokines. Paradoxically, although inflammation is an essential part of the response of the body to infection, surgery and trauma, it can adversely affect patient outcome. The metabolic effects of inflammation are mediated by pro-inflammatory cytokines. Metabolic effects include insulin insensitivity, hyperlipidaemia, muscle protein loss and oxidant stress. These effects, as well as being present during infective disease, are also present in diseases with a covert inflammatory basis. These latter diseases include obesity and type 2 diabetes mellitus. Inflammatory stress also increases during aging. The level of cytokine production, within individuals, is influenced by single nucleotide polymorphisms (SNP) in cytokine genes. The combination of SNP controls the relative level of inflammatory stress in both overt and covert inflammatory diseases. The impact of cytokine genotype on the intensity of inflammatory stress derived from an obese state is unknown. While studies remain to be done in the latter context, evidence shows that these genomic characteristics influence morbidity and mortality in infectious disease and diseases with an underlying inflammatory basis and thereby influence the cost of in-patient obesity. Antioxidants andn-3 PUFA alter the intensity of the inflammatory process. Recent studies show that genotypic factors influence the effectiveness of immunonutrients. A better understanding of this aspect of nutrient–gene interactions and of the genomic factors that influence the intensity of inflammation during disease will help in the more effective targeting of nutritional therapy.

scholarly journals Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future

2011 ◽  
Vol 2 (2) ◽  
pp. 137
Author(s):  
Chancellor E. Donald ◽  
Luis E. Raez ◽  
Edgardo S. Santos
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Head And Neck ◽  
Intracellular Signaling ◽  
Therapeutic Option ◽  
Locally Advanced ◽  
Tyrosine Kinase Domain ◽  
Epidermal Growth ◽  
The Impact ◽  
Human Epidermal Receptor

The understanding of the epidermal growth factor pathway in terms of intracellular signaling and its role in proliferation and cell survival has impacted the therapeutic management of many solid tumor malignancies in which this pathway has been dysregulated. Once the receptor is targeted at its cellular membrane level or tyrosine kinase domain, its blockage induces downregulation of oncogenic and tumorigenesis mechanisms which were in place, and thus inhibits proliferation and induces apoptosis of the malignant cell. Nowadays, we have several monoclonal antibodies as well as small molecules which target the receptor of epidermal growth factor. Although several receptors have been described within the human epidermal receptor family, our discussion will be focused on the impact of human epidermal receptor-1 as a therapeutic option for locally advanced squamous cell carcinoma of the head and neck.

scholarly journals The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1178 ◽  
Author(s):  
Megan Crumbaker ◽  
Eva K. F. Chan ◽  
Tingting Gong ◽  
Niall Corcoran ◽  
Weerachai Jaratlerdsiri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Precision Medicine ◽  
Metastatic Prostate Cancer ◽  
Parp Inhibitor ◽  
Locally Advanced ◽  
Genomic Data ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Therapeutic Decision Making ◽  
The Impact

Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease.

INCB018424, a Selective JAK1/2 Inhibitor, Significantly Improves the Compromised Nutritional Status and Frank Cachexia in Patients with Myelofibrosis (MF).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1760-1760 ◽  
Author(s):  
Ruben A. Mesa ◽  
Srdan Verstovsek ◽  
Hagop M. Kantarjian ◽  
Animesh D. Pardanani ◽  
Steven Friedman ◽  
...  
Keyword(s):  
Weight Loss ◽  
Nutritional Status ◽  
Total Cholesterol ◽  
Body Mass ◽  
Inflammatory Cytokines ◽  
Cytokine Signaling ◽  
Costal Margin ◽  
Early Satiety ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Abstract BACKGROUND: MF is a progressive illness associated with cachexia and weight loss (Mesa et al, Cancer2007;109: 68). These clinical signs, resulting from both hypercatabolism (secondary to increased pro-inflammatory cytokines) and MF associated splenomegaly, are associated with decreased survival (Dupriez et al., Blood1996;88:1013). Currently, there is no therapy that decreases the progressive cachexia of MF. INCB018424 is a selective JAK1/2 inhibitor which has the potential to improve both the aberrant myeloproliferation in MF through decreasing constitutively active JAK-STAT signaling, and nutritional status by decreasing both splenomegaly and the pathologically increased cytokines. METHODS: Symptomatic patients with MF enrolled in a phase I/II trial (www.ClinicalTrials.gov, NCT00509899) with INCB018424, were analyzed for the impact of therapy on nutritional status and cachexia. Specifically, in addition to traditional endpoints of IWG-MRT response (reported elsewhere) patients were assessed for changes in body mass index (BMI), serum cholesterol values, spleen size, and patient reports of early satiety and anorexia. Additionally, leptin, an adipose-derived protein hormone that plays a key role in regulating energy balance and circulates at levels proportional to body fat in health and disease (Mantovani et al, J Mol Med2001; 79:406), was assessed serially. RESULTS: Patients: Thirty four MF patients, treated for at least 2 months with 25 mg twice daily of INCB018424, were included in this analysis. Among this group 85% demonstrated splenomegaly (median 20 cm below left costal margin, range 4 cm to 32 cm; 2 patients had prior splenectomy) and had a median BMI of 24.8 (range 17.9 to 49.7). Although the median BMI at baseline would be considered in the “normal range” (18.5–24.9), loss of lean body mass at enrollment would be underestimated by the contribution of splenomegaly or edema. Appetite: At enrollment, a clearly positive correlation between the presence of anorexia and early satiety (by patient’s report) and significant splenomegaly was observed. Treatment with INCB018424 led to resolution of the symptoms of poor appetite and early satiety, along with the reduction in splenomegaly. Weight: MF patients on therapy initially lost weight, which reflects resolution of excess extravascular water (based on investigators reported decreases in peripheral edema, ascites, or splenomegaly). As the trial progressed MF patients on INCB018424 treatment progressively gained weight (mean increase of 0.40 kg @ 1 month, 2.93 kg @ 2 mo, 3.70 @ 3 mo), and exhibited improved appetite. Importantly, weight gain was more consistent, of greater magnitude and more durable in patients who entered the study in the lowest quartile for BMI. Cholesterol: We previously reported that hypocholesterolemia (total cholesterol <150 or 100 mg/dL; HDL < 60mg/dL) is associated with decreased survival in MF patients (Mesa et al, Blood2007; 2007;110:a2548), potentially from hypercatabolism and splenic consumption of lipids. At enrollment, median total cholesterol was 95 mg/dl (range), with 94% and 55% below 150 mg/dl and 100 mg/dl, respectively. Following treatment with INCB018424, median total cholesterol increased to 145 mg/dl (range 72–289 mg/dL) with 73% increasing to an improved range above their baseline (either to the >100mg/dl or >150 mg/dl range). Leptin: At enrollment, MF patients had very low leptin levels (mean = 2.55 ng/mL with 50% below 1 ng/mL vs. a range of 6–12 ng/mL for normal volunteers). Low plasma levels are associated with shortened survival in cancer patients. The plasma leptin levels increased 176% on average after one month of treatment with INCB018424, and continued to increase to levels matching healthy volunteers with time on study (mean = 7.04 ng/mL (range 0.25 – 35 ng/mL) after 2 months on INCB018424) and correlated to weight increases. CONCLUSIONS: Therapy with INCB018424 improves the nutritional status of MF patients, including improving pathologic weight loss, hypercatabolism associated hypocholesterolemia, and pathologically decreased serum leptin. The improved nutritional status of MF patients treated with INCB018424 may reflect the ability of JAK inhibition to target the underlying pathophysiology of MF cachexia by reducing the organomegaly, levels of pro-inflammatory cytokines, and pro-inflammatory cytokine signaling.

Pro-Inflammatory Cytokines Drive the Development of a Prothrombotic Platelet Phenotype in Inflammation and Aging

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3747-3747 ◽  
Author(s):  
Pavel Davizon-Castillo ◽  
Katrina Ashworth ◽  
Kelly Higa ◽  
Giovanny Hernandez ◽  
Sumitra Acharya ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Inflammatory Cytokines ◽  
Platelet Function ◽  
Inflammatory Cytokine ◽  
Inflammatory Diseases ◽  
Hematopoietic Stem ◽  
Activation Profile ◽  
The Impact ◽  
Old Mice ◽  
Pro Inflammatory Cytokines

Abstract A high incidence of thrombotic events remains a potentially life-threatening consequence in a broad range of chronic inflammatory conditions including infection, obesity, cardiovascular disease (CVD), autoimmune disorders and aging. While deregulation of pro-coagulant molecules and activation of endothelial surfaces have been described as contributors to such thrombotic events, the extent to which the pro-inflammatory cytokine environment associated with inflammatory diseases may impact platelet reactivity, production and function remains to be further characterized. Hence, to directly interrogate the impact of inflammation on platelet function, we analyzed the platelet activation profile of washed platelets by flow cytometry using murine models of rheumatoid arthritis, collagen-induced arthritis (CIA) and of aging (24 month-old mice) to identify inflammation-induced changes in platelet function and production. Notably, both models revealed significant alterations to platelet function, characterized by increased exposure of P-selectin and the active form of the integrin aIIbb3 (JON/A) following platelet activation with thrombin. In addition, the exposure of phosphatidylserine (PS), measured with Lactadherin binding, was elevated in platelets from chronically inflamed CIA and old mice. As the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNF) are key mediators of chronic inflammatory disease, we assessed using Tnf ΔARE transgenic mice, which overexpress TNF-α as well as young mice treated with daily injections of rIL1- for 20 days, whether chronic exposure these cytokines is sufficient to alter platelet function. Strikingly, despite increased peripheral blood platelet numbers, IL-1β treated mice did not exhibit a hyper-reactive platelet phenotype when compared to controls. On the other hand, platelets from Tnf ΔARE mice showed significant hyperactivity, and a single dose (24 hours) of murine rTNF or in vitro culture with rTNF also induced a robust platelet activation profile, suggesting that TNF acts directly on platelets and may play a more significant role than IL-1 in the development of an inflammation-driven prothrombotic platelet phenotype. Moreover, analysis of the hematopoietic stem cell (HSC) compartment in CIA and old mice revealed an increased frequency of previously-described CD41+ megakaryocyte-biased HSCs, which is recapitulated in mice chronically exposed to IL-1, suggesting that reprogramming of HSCs by pro-inflammatory cytokines likely fuels the overproduction of hyperactive platelets that contribute to thrombosis in chronic inflammatory diseases. Collectively, our findings suggest that IL-1 and TNFα contribute to inflammation-associated thrombosis via distinct mechanisms, with TNFα playing a particularly important role in platelet hyperactivation, and IL-1 impacting platelet production, likely in part via modulation of HSC fate. Hence, our findings identify a key role for distinct cytokine circuits in regulating platelet function, and implicate the pro-inflammatory cytokine environment as a key therapeutic target for modulation in patients at risk for inflammation-associated thrombotic events. Disclosures Di Paola: CSL BEhring: Consultancy; Biogen: Consultancy.

The Impact of Physical Activity on Serum Inflammatory Markers in Overweight Pubertal Boys: 24-Month Follow-Up Study

2018 ◽  
Vol 30 (2) ◽  
pp. 198-207
Author(s):  
Liina Remmel ◽  
Vallo Tillmann ◽  
Eva Mengel ◽  
Pille Kool ◽  
Priit Purge ◽  
...  
Keyword(s):  
Physical Activity ◽  
Growth Factor ◽  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Vigorous Physical Activity ◽  
Interferon Γ ◽  
Active Group ◽  
Chemotactic Protein ◽  
Factor Α ◽  
The Impact

Purpose: To investigate the differences in the pattern of changes in serum inflammatory cytokines measured annually over a 24-month period, between less active and more active overweight boys. Participants/Methods: In total, 25 pubertal overweight boys were divided by their moderate to vigorous physical activity (MVPA) levels into 2 groups: less active group (LAG; n = 10; MVPA < 60 min/d) and more active group (MAG; n = 15; MVPA > 60 min/d). Physical activity was measured by 7-day accelerometry. Serum concentration of 13 inflammatory cytokines [interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1β, vascular endothelial growth factor, interferon-γ, tumor necrosis factor-α, monocyte chemotactic protein-1, epidermal growth factor, and C-reactive protein] was measured at baseline (T0), after 12 months (T1), and after 24 months (T2) from fasting blood samples. Results: Serum IL-6 level was significantly higher [LAG: 1.27 (0.86, 1.98) pg/mL; MAG: 0.80 (0.52, 0.84) pg/mL] at T0 and IL-8 level [LAG: 10.26 (8.80, 11.64) pg/mL; MAG: 7.42 (6.10, 9.54) pg/mL] at T2 in LAG compared with MAG. The changes over the study period varied between different inflammatory markers. None of the slopes of any measured markers were statistically different between the LAG and MAG, although the slopes of interferon-γ and IL-10 tended to be different between the groups. Conclusions: The pattern of changes over the study period varied between different inflammatory markers, but these changes were not different between the MVPA groups. More longitudinal studies are needed to investigate whether IL-6, IL-8, IL-10, and interferon-γ would be the choice of inflammatory markers to study the associations between obesity and physical activity in future.

scholarly journals The Impact of Immunological Factors on Depression Treatment – Relation Between Antidepressants and Immunomodulation Agents

2019 ◽  
Vol 7 (18) ◽  
pp. 3064-3069 ◽  
Author(s):  
Jovana Vojvodic ◽  
Goran Mihajlovic ◽  
Petar Vojvodic ◽  
Dusan Radomirovic ◽  
Aleksandra Vojvodic ◽  
...  
Keyword(s):  
Immune System ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Signal Pathways ◽  
Depression Treatment ◽  
Residual Symptoms ◽  
Immunological Mechanisms ◽  
Anti Inflammatory ◽  
The Impact

It is determined that 30% of patients with depression are resistant to antidepressant medication. The increased concentration of inflammation factors, such as C-reactive protein, and pro-inflammatory cytokines, have been detected in serum in these patients. It is necessary to establish new therapeutic possibilities and protocols that are created to overcome the difficulties caused by increased concentration of inflammatory biomarkers in depressive patients. The Selective Serotonin Reuptake Inhibitors (SSRIs) are considered to be the most powerful antidepressants, increasing the level of serotonin in endogenous depression, as well as in that caused by immunological mechanisms. It is believed that agents that influence cytokines, immunological signal pathways and cytokine syntheses, like the inhibitors of cyclooxygenase enzyme and other non-steroidal anti-inflammatory drugs (NSAIDs), are very important in the potential treatment of residual symptoms of depression. Treatment with cytokine antagonists is one of the potential adjuvant therapies, along with antidepressants. Signal pathways blockers, such as the inhibitors of cyclooxygenase and other NSAIDs, are in the phase of research, in terms of their antidepressant effects. Also, it has been shown that the inhibition of indolamin-2,3 deoxygenase (IDO) and kynurenine (KYN) signal pathways in the synthesis of neurotransmitters, by application of IDO antagonists, are leading to suppression of pro-inflammatory cytokine effects. Antidepressants may have anti-inflammatory effects, depending on dose and type, and they achieve this effect through the decrease of pro-inflammatory cytokine production and increase of anti-inflammatory cytokines. Also, antidepressants modulate the humoral and cellular immune system. This work aims to summarise certain neurobiological and neuroimmunological specificities that have been observed in patients with depression, antidepressants and immunomodulation agents. The understanding of complex and heterogenic pathophysiology of depression through the prism of the altered immune system, is of major importance, in terms of better optimisation of pharmacotherapy, and options for a personalised approach in depressive disorder treatment.

Phase II trial of a PARP inhibitor in somatic BRCA mutant metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1113-TPS1113
Author(s):  
Neelima Vidula ◽  
Nora K. Horick ◽  
Erica Blouch ◽  
Amalia Rivera ◽  
Erin Basile ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Massachusetts General Hospital ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibition ◽  
The Impact

TPS1113 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are now approved for patients with germline BRCA1/2 mutated HER2 negative metastatic breast cancer (MBC). However, germline BRCA1/2 mutations only account for 5-10% of breast cancer. We previously demonstrated that a subset of MBC may harbor somatic BRCA1/2 mutations detectable by cell-free DNA (cfDNA) (Vidula, SABCS, 2017). We hypothesize that somatic BRCA1/2 mutant MBC may also respond to PARP inhibition, similar to ovarian cancer, where PARP inhibition is efficacious in both somatic and germline tumors (Oza, 2017). Methods: This single arm, open label, phase II clinical trial is evaluating the efficacy of talazoparib, a PARP inhibitor, in 30 patients with somatic pathogenic BRCA1/2 mutant MBC identified by cfDNA. Patients may have triple-negative disease with receipt of at least 1 prior chemotherapy regimen, or hormone receptor positive, HER2 negative disease with at least 1 prior hormone therapy for MBC. Patients may have received a prior platinum, in the absence of progression on platinum chemotherapy. Patients must not have a known germline BRCA1/2 mutation. Patients will be treated with talazoparib 1 mg daily until progression, unacceptable toxicity, or withdrawal of consent, with clinical exams monthly, scans (CT chest, abdomen, and pelvis, and bone scan as appropriate) every 3 months, and serial cfDNA collected monthly. The primary endpoint is progression-free survival, as defined by RECIST 1.1. Subjects are enrolled in a 2-stage design, which provides 80% power to demonstrate that treatment is associated with “success” (PFS > 12 weeks) in ³ 53% patients (4% alpha). Additional endpoints include objective response rate and toxicity (per NCI CTCAE version 5.0). Correlative endpoints include determining changes in BRCA1/2 mutant allele fraction, genomic evolution including emergence of BRCA reversion mutations, and the impact of biomarker changes on outcomes. This trial is currently enrolling patients at the Massachusetts General Hospital. Successful completion of this study may help expand the patient population that is able to benefit from PARP inhibition. Clinical trial information: NCT03990896 .

scholarly journals SILAC proteomics implicates the ubiquitin conjugating enzyme UBE2D in SOCS1-mediated downmodulation of the MET receptor in hepatocytes

2020 ◽  
Author(s):  
Madanraj Appiya Santharam ◽  
Akhil Shukla ◽  
Awais Ullan Ihsan ◽  
Maryse Cloutier ◽  
Dominique Levesque ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Growth Factor ◽  
Sh2 Domain ◽  
Mass Spectrometry Analysis ◽  
Cytokine Signaling ◽  
Spectrometry Analysis ◽  
Mitochondrial Ribosome ◽  
Ubiquitin Conjugating Enzyme ◽  
The Impact ◽  
Conjugating Enzyme

AbstractSuppressor of Cytokine Signaling 1 (SOCS1) functions as a tumor suppressor in hepatocellular carcinoma (HCC) and many other types of cancers. SOCS1 mediates its functions by inhibiting tyrosine kinases, promoting ubiquitination and proteasomal degradation of signal transducing proteins, and by modulating transcription factors. Here, we studied the impact of SOCS1 on the hepatocyte proteome using Stable Isotopic Labelling of Amino acids in Cell culture (SILAC)-based mass spectrometry on the Hepa1-6 murine HCC cell line stably expressing wildtype SOCS1 or a mutant SOCS1 with impaired SH2 domain. As SOCS1 regulates the hepatocyte growth factor (HGF) receptor MET, the SILAC-labelled cells were stimulated or not with HGF. Following mass spectrometry analysis, differentially modulated proteins were identified, quantified and analyzed for pathway enrichment. Of the 3440 proteins identified in Hepa-SOCS1 cells at steady state, 181 proteins were significantly modulated compared to control cells. The SH2 domain mutation and HGF increased the number of differentially modulated proteins. Protein interaction network analysis revealed enrichment of SOCS1-modulated proteins within multiprotein complexes such as ubiquitin conjugating enzymes, proteasome, mRNA spliceosome, mRNA exosome and mitochondrial ribosome. These findings suggest that SOCS1, induced by cytokines, growth factors and diverse other stimuli, may dynamically modulate of large macromolecular regulatory complexes to help maintain cellular homeostasis. Notably, the expression of UBE2D ubiquitin conjugating enzyme, which is implicated in the control of growth factor receptor tyrosine kinase signaling, was found to be regulated by SOCS1.

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