• CD47
• GW501516
• Immune escape
• PPARδ
• Transcription

• Phagocytosis/drug effects
• Animals
• CD47 Antigen/genetics
• CD47 Antigen/metabolism
• Humans
• PPAR delta/agonists
• PPAR delta/genetics
• PPAR delta/metabolism
• Mice
• Colonic Neoplasms/immunology
• Colonic Neoplasms/pathology
• Colonic Neoplasms/drug therapy
• Thiazoles/pharmacology
• Tumor Escape/drug effects
• Cell Line, Tumor
• Macrophages/drug effects
• Macrophages/immunology
• Gene Expression Regulation, Neoplastic/drug effects

• colorectal cancer

• 2024-MS-281 Natural Science Foundation of Liaoning Province (Liaoning Provincial Natural Science Foundation)
• Science and Technology Innovation Fund Project of Dalian (2023JJ13SN050) Xingliao Talents Program(Zhe Fan)

• PPARs
• anti-cancer therapy
• cancer
• metabolic reprogramming
• tumor microenvironment

Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.

• PPAR
• angiogenesis
• cell proliferation
• cellular metabolism
• immune surveillance
• metastasis
• resistance to cell death
• tumor growth suppressors

• Fatty Acids/metabolism
• Humans
• Ligands
• Neoplasms
• PPAR alpha
• PPAR delta
• PPAR-beta
• Peroxisome Proliferator-Activated Receptors/metabolism

• AMPK
• PPARδ
• cancer
• misfolded protein
• phosphorylation

• Adenylate Kinase/metabolism
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Female
• Glucose/metabolism
• Glutamine/metabolism
• Heterografts
• Humans
• Mice, Nude
• PPAR gamma/metabolism
• Phosphorylation
• Mice

PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. Three different isoforms, PPAR alpha, PPAR beta/delta and PPAR gamma have been identified. They all form heterodimers with retinoic X receptors to activate or repress downstream target genes dependent on the presence/absence of ligands and coactivators or corepressors. PPARs differ in their tissue expression profile, ligands and specific agonists and antagonists. PPARs attract attention as potential therapeutic targets for a variety of diseases. PPAR alpha and gamma agonists are in clinical use for the treatment of dyslipidemias and diabetes. For both receptors, several clinical trials as potential therapeutic targets for cancer are ongoing. In contrast, PPAR beta/delta has been suggested as a therapeutic target for metabolic syndrome. However, potential risks in the settings of cancer are less clear. A variety of studies have investigated PPAR beta/delta expression or activation/inhibition in different cancer cell models in vitro, but the relevance for cancer growth in vivo is less well documented and controversial. In this review, we summarize critically the knowledge of PPAR beta/delta functions for the different hallmarks of cancer biological capabilities, which interplay to determine cancer growth.

• angiogenesis
• cellular metabolism
• growth suppressors
• immortality
• immune system
• metastasis
• peroxisome proliferator-activated receptor
• proliferation
• resistance to cell death

• Animals
• Apoptosis
• Cellular Senescence
• Humans
• Neoplasms/blood supply
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic/metabolism
• PPAR delta/metabolism
• PPAR-beta/metabolism

• cancer metabolism
• energy metabolism
• nuclear receptors

Hepatitis B X-interacting protein (HBXIP, also termed as LAMTOR5) plays a crucial role in regulation of cancer progression, while the mechanism is still unclear. Here we found that HBXIP increased the expression of PPARδ (peroxisome proliferator-activated receptor-δ) in gene and protein levels of SW480 or HT-29 colonic cancer cells. Chromatin immunoprecipitation and luciferase reporter assays showed that HBXIP occupied the core promoter (−1079/−239 nt) regions of PPARδ and that HBXIP activated the transcription activity of PPARδ in an NF-κB (p65)-dependent manner. Moreover, Co-immunoprecipitation and immunofluorescence analysis showed that HBXIP bound to NF-κB/p65 in the cells. Interestingly, we found that PPARδ could conversely increase the expression of NF-κB/p65 through activating its transcription activity. In addition, the clinical observations showed that both HBXIP and PPARδ were highly expressed in colonic carcinoma, and HBXIP expression was positively associated with that of PPARδ in the clinical specimen. Importantly, HBXIP expression levels were positively correlated with the clinical pathological parameters including lymph node metastasis and advanced TNM stage. These findings suggest that HBXIP served as a co-activator to activate the positive feedback regulations of NF-κB/PPARδ, which promoted the fast proliferation of the colonic cancer cells. Therapeutically, HBXIP may serve as a potential drug target of colonic cancer cells.

• HBXIP
• NF-κB
• PPARδ
• colonic cancer
• proliferation

The occurrence and development of colon cancer is closely related to inflammation. Therefore, this study was conducted a current retrospective research to study the effect of IL-35 (interleukin 35), a newly identified anti-infective factor, on colon cancer development. The expression of IL-35 in colon cancer samples and their adjacent normal mucosa by real-time PCR, ELISA (enzyme-linked immunosorbent assay). The effect of IL-35 on patient survival, colon cancer progression, and its effect on Wnt/β-catenine signaling pathway was also assessed. IL-35 is minimally expressed in colon cancer tissues but is highly expressed in adjacent normal tissues. The down-regulation of IL-35 was significantly associated with the American Cancer Joint Committee stage and overall survival of colon cancer patients. The overexpression of IL-35 in colon cancer cells inhibits cell migration, invasion, proliferation, colony formation and cancer stem cells by inhibiting beta-catenin. IL-35 inhibits colon neoplasms in mouse. Our results suggest that IL-35 has an inhibitory effect on the development of colon cancer as a novel prognostic indicator and potential therapeutic target.

• IL-35
• colon cancer
• inhibition
• metastasis
• β-catenin

• cardiac repair
• cardiomyocyte proliferation
• screening
• carbacyclin
• pparδ
• gsk3β
• tbx20

• Animals
• Cardiomyopathies/drug therapy
• Cardiomyopathies/metabolism
• Cardiomyopathies/pathology
• Cell Proliferation/drug effects
• Epoprostenol/analogs & derivatives
• Epoprostenol/pharmacology
• Myocardium/metabolism
• Myocardium/pathology
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• PPAR delta/metabolism
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• Zebrafish/embryology
• Zebrafish Proteins/metabolism

• P30 DK079626 NIDDK NIH HHS
• R01 HL135336 NHLBI NIH HHS
• R03 AG055899 NIA NIH HHS

Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors including PPARα, PPARδ and PPARγ, which play an important role in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. In this review, we summarized the regulative mechanism of PPARs on cancer progression.

• PPARs
• cancer therapy
• cell signaling
• ligands

The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with the development and progression of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Therefore, we investigated whether oral administration of sulforaphane (SFN) prevented high-fat diet-induced NAFLD in mice by regulation of the NLRP3 inflammasome in the liver. Daily oral administrations of SFN reduced hepatic steatosis scores, serum ALT and AST levels, and hepatic levels of cholesterol, triglycerides, and free fatty acids in mice fed a high-fat diet. These were correlated with the suppression of NLRP3 inflammasome activation in the liver by SFN as evidenced by decrease in mRNA levels of ASC and caspase-1, caspase-1 enzyme activity, and IL-1β levels. SFN inhibited saturated fatty acid-induced activation of the NLRP3 inflammasome in primary mouse hepatocytes, accompanied by the restoration of mitochondrial dysfunction. The suppression of NLRP3 inflammasome by SFN was mediated by the regulation of AMP-activated protein kinase-autophagy axis. Our findings demonstrated that the suppression of NLRP3 inflammasome activation by an orally available small molecule inhibitor leads to the alleviation of the hepatic steatosis symptoms associated with NAFLD induced by a high-fat diet.

Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.

• Eicosanoids
• Cyclooxygenase
• Lipoxygenase
• Inflammation
• Colorectal cancer

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Antineoplastic Agents/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Eicosanoids/metabolism
• Fatty Acids, Unsaturated/metabolism
• Humans
• Inflammation/drug therapy
• Inflammation/metabolism
• Inflammation/pathology
• Molecular Targeted Therapy
• Signal Transduction/drug effects
• Tumor Microenvironment

• Celastrol (PubChem CID: 122724)
• Dithiothreitol (PubChem CID: 446094)
• Inflammation
• Innate immune signaling
• Ligand binding to receptor
• Lipopolysaccharide (PubChem CID: 11970143)
• Macrophages
• N-Acetyl-(L)-cysteine (PubChem CID: 12035)
• Pattern-recognition receptor

• Acetylcysteine/pharmacology
• Animals
• Anti-Inflammatory Agents/isolation & purification
• Anti-Inflammatory Agents/pharmacology
• Cytokines/metabolism
• Dithiothreitol/pharmacology
• Enzyme-Linked Immunosorbent Assay
• Lipopolysaccharides/metabolism
• Lymphocyte Antigen 96/metabolism
• Macrophages/drug effects
• Macrophages/metabolism
• Medicine, Chinese Traditional
• Mice
• Mice, Inbred C57BL
• Pentacyclic Triterpenes
• Polymerase Chain Reaction
• Sulfhydryl Compounds/chemistry
• Toll-Like Receptor 4/metabolism
• Tripterygium/chemistry
• Triterpenes/isolation & purification
• Triterpenes/pharmacology

Immunotherapy has been extensively pursed as a promising strategy for the treatment of cancer. Pattern-recognition receptors (PRRs) play important roles in triggering activation of innate and adaptive immunity. Therefore, agents that stimulate PRRs could be useful for cancer immunotherapy. We developed two kinds of X-shaped double-stranded oligodeoxynucleotides (X-DNA), a single unit of X-DNA (X_S-DNA) composed of four strands of DNA and a ligated X-DNA complex (X_L-DNA) formed by crosslinking each X_S-DNA to the other, and investigated if they had immunostimulatory activity and could be applied to anti-cancer immunotherapy.

Activation of MAPKs and NF-κB was determined by immunoblotting in bone marrow-derived primary dendritic cells (BMDCs). Immune cytokines and co-stimulatory molecules were measured by ELISA and flow cytometry analysis. Anti-cancer efficacy was examined in an azoxymethane/dextran sulfate sodium-induced colitis-associated colon cancer mouse model. Association of X-DNA and TLR9 was determined by co-immunoprecipitation followed by immunoblotting. The involvement of TLR9 and inflammasomes was determined using TLR9- or caspase-1-deficient BMDCs. Inflammasome activation was examined by degradation of pro-caspase-1 to caspase-1 and cleavage of pro-IL-1β to IL-1β in BMDCs.

X_L-DNA and X_S-DNA induced activation of MAPKs and NF-κB and production of immune cytokines and co-stimulatory molecules in BMDCs. BMDCs stimulated by X_L-DNA induced differentiation of naïve CD4⁺ T cells to T_H1 cells. Intravenous injection of X_L-DNA into mice resulted in increased serum IFN-γ and IL-12 levels, showing in vivo efficacy of X_L-DNA to activate T_H1 cells and dendritic cells. X_L-DNA greatly enhanced the therapeutic efficacy of doxorubicin, an anti-cancer drug, in colitis-associated colon cancer. X_L-DNA directly associated with TLR9. In addition, immunostimulatory activities of X-DNA were abolished in TLR9-deficient dendritic cells. Furthermore, X-DNA induced caspase-1 degradation and IL-1β secretion in BMDCs, which were abolished in caspase-1-deficient cells.

X-DNA induced the activation of dendritic cells as shown by the expression of immune-cytokines and co-stimulatory molecules, resulting in the differentiation of T_H1 cells, mediated through dual activation of TLR9 and inflammasomes. X-DNA represents a promising immune adjuvant that can enhance the therapeutic efficacy of anti-cancer drugs by activating PRRs.

The online version of this article (doi:10.1186/s12943-015-0369-2) contains supplementary material, which is available to authorized users.

• innate immunity
• macrophages
• pattern-recognition receptor
• type I interferon
• virus infection

• Bacterial infection
• Immune-suppression
• LPS
• MD2
• Phytochemical
• Toll-like receptor