scholarly journals β-Catenin Regulation in Sporadic Colorectal Carcinogenesis: Not as Simple as APC

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Ernst Fredericks ◽  
Gill Dealtry ◽  
Saartjie Roux
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Statistical Significance ◽  
Inhibitory Effect ◽  
Colorectal Carcinogenesis ◽  
Sporadic Colorectal Cancer ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cox 2

Background. The wnt/APC/β-catenin pathway is a critical initiator in colorectal carcinogenesis in both hereditary and sporadic colorectal cancer (CRC). The progression of this process remains incompletely understood, although inflammation is pivotal. Drivers of inflammation are elevated in malignant tissue and have been shown to regulate β-catenin expression. Interleukin-17A (IL-17A) is protumorigenic at elevated levels via COX-2 stimulation. Elevated peroxisome proliferator-activated receptor γ (PPARγ) expression has reduced risk of carcinogenesis and good overall prognosis in established CRC. Activation of PPARγ has inhibitory effect on β-catenin. Methods. Using qPCR and IHC, we compared β-catenin, PPARγ, COX-2, and IL-17A in the colonic mucosa of patients with sporadic CRC, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS), against a normal control population. Results. β-catenin mRNA and protein expression progressively increased from the Normal group, through IBS and IBD reaching statistical significance in CRC. COX-2 mRNA levels increased similarly with statistical significance in IBD and CRC. However, COX-2 protein expression was inverted with significant expression in the Normal and IBS groups and reduced levels in IBD and CRC. PPARγ mRNA expression was unchanged in IBD and CRC but was significantly elevated in the IBS. IL-17A mRNA was significantly reduced in IBS and CRC but unchanged in IBD. There were no differences in all parameters tested in the Normal and IBS groups. Conclusion. β-catenin is confirmed as a major driver of colorectal carcinogenesis but is controlled by many more players other than APC. Elevated levels of PPARγ may have an anticarcinogenic effect. The role of COX-2 expression, especially its posttranscriptional regulation in colorectal cancer, needs further elucidation.

scholarly journals RAPID COMMUNICATION: Inhibitory Effect of Pioglitazone on Carotid Arterial Wall Thickness in Type 2 Diabetes

2001 ◽  
Vol 86 (7) ◽  
pp. 3452-3452 ◽  
Author(s):  
Hiroyuki Koshiyama ◽  
Dai Shimono ◽  
Naomitsu Kuwamura ◽  
Jun Minamikawa ◽  
Yoshio Nakamura
Keyword(s):  
Type 2 Diabetes ◽  
Statistical Significance ◽  
Intima Media Thickness ◽  
Inhibitory Effect ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Carotid Arterial

There have been increasing evidences that thiazolidinediones, peroxisome proliferator-activated receptor γ (PPARγ) agonists, may have some antiatherogenic actions. We have previously reported that troglitazone has a potent inhibitory effect on common carotid arterial intima-media thickness (IMT) in subjects with type 2 diabetes. However, some studies suggested a possibility that PPARγ activators may have protoatherogenic actions, raising concern about their detrimental effects in diabetic subjects. In the present study, we investigated the effect of treatment with pioglitazone, another PPARγ agonist, on IMT in a total of 106 Japanese subjects with type 2 diabetes. Pioglitazone (30 mg daily) was administered for 6 months in 53 patients. Compared to control group (n = 53), the group given pioglitazone showed a significant decrease in IMT as early as 3 months after the administration. The decrease in IMT was also found after 6 months (IMT change: −0.084[SE 0.023] mm vs. control 0.022[SE 0.006] mm, P < 0.001), although the difference between those after 3 and 6 months did not reach any statistical significance. These findings indicate that thiazolidinediones cause an inhibition of early atherosclerotic process PPARγ activation.

scholarly journals PPARγLigand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Hirokazu Takahashi ◽  
Kunihiro Hosono ◽  
Takashi Uchiyama ◽  
Michiko Sugiyama ◽  
Eiji Sakai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pilot Study ◽  
Surrogate Marker ◽  
Aberrant Crypt Foci ◽  
Colorectal Carcinogenesis ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Promising Candidate ◽  
Peroxisome Proliferator Activated Receptor ◽  
Magnifying Colonoscopy

Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARγ), such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARγligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF) have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day) group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8±1.1to3.3±2.3) after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARγligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.

scholarly journals The Expression/Methylation Profile of Adipogenic and Inflammatory Transcription Factors in Adipose Tissue Are Linked to Obesity-Related Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1629 ◽  
Author(s):  
Hatim Boughanem ◽  
Amanda Cabrera-Mulero ◽  
Pablo Hernández-Alonso ◽  
Borja Bandera-Merchán ◽  
Alberto Tinahones ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adipose Tissue ◽  
Transcription Factors ◽  
Visceral Adipose Tissue ◽  
Critical Role ◽  
Colorectal Carcinogenesis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obese Control ◽  
Visceral Adipose

Obesity is well accepted as crucial risk factor that plays a critical role in the initiation and progression of colorectal cancer (CRC). More specifically, visceral adipose tissue (VAT) in people with obesity could produce chronic inflammation and an altered profile expression of key transcription factors that promote a favorable microenvironment to colorectal carcinogenesis. For this, the aim of this study was to explore the relationship between adipogenic and inflammatory transcription factors in VAT from nonobese, obese, and/or CRC patients. To test this idea, we studied the expression and methylation of CCAAT-enhancer binding protein type alpha (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in VAT from non-obese control, non-obese CRC subjects, overweight/obese control, and overweight/obese CRC patients and their correlation with anthropometric and biochemical variables. We found decreased expression of C/EBP-α in overweight/obese CRC patients in comparison with overweight/obese control subjects. PGC-1α and NF-κB were overexpressed in CRC patients independently of the BMI. NF-κB promoter was hypomethylated in overweight/obese CRC patients when compared to overweight/obese control individuals. In addition, multiple significant correlations between expression, methylation, and biochemical parameters were found. Finally, linear regression analysis showed that the expression of C/EBP-α and NF-κB and that NF-κB methylation were associated with CRC and able to explain up to 55% of CRC variability. Our results suggest that visceral adipose tissue may be a key factor in tumor development and inflammatory state. We propose C/EBP-α, PGC-1α and NF-κB to be interesting candidates as potential biomarkers in adipose tissue for CRC patients.

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

2020 ◽  
Vol 27 ◽  
Author(s):  
Rana A. Alaaeddine ◽  
Perihan A. Elzahhar ◽  
Ibrahim AlZaim ◽  
Wassim Abou-Kheir ◽  
Ahmed S.F. Belal ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Targets ◽  
Design And Synthesis ◽  
Early Results ◽  
Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

scholarly journals BST204 Protects Dexamethasone-Induced Myotube Atrophy through the Upregulation of Myotube Formation and Mitochondrial Function

2021 ◽  
Vol 18 (5) ◽  
pp. 2367
Author(s):  
Ryuni Kim ◽  
Hyebeen Kim ◽  
Minju Im ◽  
Sun Kyu Park ◽  
Hae Jung Han ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dry Extract ◽  
Myotube Formation ◽  
Species Production

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

scholarly journals Zidovudine Impairs Adipogenic Differentiation through Inhibition of Clonal Expansion

2008 ◽  
Vol 52 (8) ◽  
pp. 2882-2889 ◽  
Author(s):  
Metodi V. Stankov ◽  
Reinhold E. Schmidt ◽  
Georg M. N. Behrens
Keyword(s):  
Adipogenic Differentiation ◽  
Clonal Expansion ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triglyceride Accumulation ◽  
Thymidine Incorporation Assay ◽  
Human Preadipocytes ◽  
Incorporation Assay ◽  
The Impact

ABSTRACT Lipoatrophy is a prevalent side effect of treatment with thymidine analogues. We wished to confine the time point of the antiadipogenic effect of zidovudine (AZT) during adipogenesis and to evaluate the antiproliferative effect of AZT on adipocyte homeostasis. We investigated the effects of AZT on adipogenesis in 3T3-F442A cells and studied their proliferation, differentiation, viability, and adiponectin expression. Cells were exposed to AZT (1 μM, 3 μM, 6 μM, and 180 μM), stavudine (d4T; 3 μM), or dideoxycytosine (ddC; 0.1 μM) for up to 15 days. Differentiation was assessed by real-time PCR and quantification of triglyceride accumulation. Proliferation and clonal expansion were determined by a [3H]thymidine incorporation assay. When they were induced to differentiate in the presence of AZT at the maximum concentration in plasma (C max) and lower concentrations, 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the later adipogenic transcription factors, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ. AZT exerted an inhibitory effect on the completion of the mitotic clonal expansion, which resulted in incomplete 3T3-F442A differentiation and, finally, a reduction in the level of adiponectin expression. In addition, AZT impaired the constitutive proliferation in murine and primary human subcutaneous preadipocytes. In contrast, incubation with d4T and ddC at the C max did not affect either preadipocyte proliferation or clonal expansion and differentiation. We conclude that the antiproliferative and antiadipogenetic effects of AZT on murine and primary human preadipocytes reveal the impact of the drug on fat tissue regeneration. These effects of the drug are expected to contribute to disturbed adipose tissue homeostasis and to be influenced by differential drug concentration and penetration in individual patients.

Thyroid hormone is required for the phenotype transitions induced by the pharmacological inhibition of calcineurin in adult soleus muscle of rats

2008 ◽  
Vol 294 (1) ◽  
pp. E69-E77 ◽  
Author(s):  
Nathalie Koulmann ◽  
Lahoucine Bahi ◽  
Florence Ribera ◽  
Hervé Sanchez ◽  
Bernard Serrurier ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Soleus Muscle ◽  
Hormone Deficiency ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Thyroid State ◽  
Novel Approach ◽  
A Subunit ◽  
Calcineurin Inhibition

The present experiment was designed to examine the effects of hypothyroidism and calcineurin inhibition induced by cyclosporin A (CsA) administration on both contractile and metabolic soleus muscle phenotypes, with a novel approach to the signaling pathway controlling mitochondrial biogenesis. Twenty-eight rats were randomly assigned to four groups, normothyroid, hypothyroid, and orally treated with either CsA (25 mg/kg, N-CsA and H-CsA) or vehicle (N-Vh and H-Vh), for 3 wk. Muscle phenotype was estimated by the MHC profile and activities of oxidative and glycolytic enzymes. We measured mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the major regulator of mitochondrial content. We also studied the expression of the catalytic A-subunit of calcineurin (CnA) both at protein and transcript levels and mRNA levels of modulatory calcineurin inhibitor proteins (MCIP)-1 and -2, which are differentially regulated by calcineurin activity and thyroid hormone, respectively. CsA-administration induced a slow-to-fast MHC transition limited to the type IIA isoform, which is associated with increased oxidative capacities. Hypothyroidism strongly decreased both the expression of fast MHC isoforms and oxidative capacities. Effects of CsA administration on muscle phenotype were blocked in conditions of thyroid hormone deficiency. Changes in the oxidative profile were strongly related to PGC-1α changes and associated with phosphorylation of p38 MAPK. Calcineurin and MCIPs mRNA levels were decreased by both hypothyroidism and CsA without additive effects. Taken together, these results suggest that adult muscle phenotype is primarily under the control of thyroid state. Physiological levels of thyroid hormone are required for the effects of calcineurin inhibition on slow oxidative muscle phenotype.

scholarly journals Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography

2015 ◽  
Vol 8s1 ◽  
pp. CGM.S21216 ◽  
Author(s):  
Susan LeGendre-McGhee ◽  
Photini S. Rice ◽  
R. Andrew Wall ◽  
Kyle J. Sprute ◽  
Ramireddy Bommireddy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Rate ◽  
Optical Coherence Tomography ◽  
Mouse Model ◽  
Tumor Burden ◽  
Colorectal Carcinogenesis ◽  
Optical Coherence ◽  
Ki 67 ◽  
Tumor Number ◽  
Cox 2

Optical coherence tomography (OCT) is a high-resolution, nondestructive imaging modality that enables time-serial assessment of adenoma development in the mouse model of colorectal cancer. In this study, OCT was utilized to evaluate the effectiveness of interventions with the experimental antitumor agent α-difluoromethylornithine (DFMO) and a nonsteroidal anti-inflammatory drug sulindac during early [chemoprevention (CP)] and late stages [chemotherapy (CT)] of colon tumorigenesis. Biological endpoints for drug interventions included OCT-generated tumor number and tumor burden. Immunochistochemistry was used to evaluate biochemical endpoints [Ki-67, cleaved caspase-3, cyclooxygenase (COX)-2, β-catenin]. K-Ras codon 12 mutations were studied with polymerase chain reaction-based technique. We demonstrated that OCT imaging significantly correlated with histological analysis of both tumor number and tumor burden for all experimental groups ( P < 0.0001), but allows more accurate and full characterization of tumor number and burden growth rate because of its time-serial, nondestructive nature. DFMO alone or in combination with sulindac suppressed both the tumor number and tumor burden growth rate in the CP setting because of DFMO-mediated decrease in cell proliferation (Ki-67, P < 0.001) and K-RAS mutations frequency ( P = 0.04). In the CT setting, sulindac alone and DFMO/sulindac combination were effective in reducing tumor number, but not tumor burden growth rate. A decrease in COX-2 staining in DFMO/sulindac CT groups (COX-2, P < 0.01) confirmed the treatment effect. Use of nondestructive OCT enabled repeated, quantitative evaluation of tumor number and burden, allowing changes in these parameters to be measured during CP and as a result of CT. In conclusion, OCT is a robust minimally invasive method for monitoring colorectal cancer disease and effectiveness of therapies in mouse models.

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