-
Biological & Pharmaceutical Bulletin 2022Lung cancer is the leading cause of cancer-related deaths worldwide. Troglitazone (TGZ), a peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is a...
Lung cancer is the leading cause of cancer-related deaths worldwide. Troglitazone (TGZ), a peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is a potential antitumor agent. However, the action mechanism of TGZ in lung adenocarcinoma cells has not been completely elucidated. To assess this mechanism and the anticancer effects of TGZ in human lung adenocarcinoma cell lines (A549 and H1975), we investigated the involvement of PPARγ, apoptosis, the mitogen-activated protein kinase (MAPK) pathway, protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, and autophagy. Cell viability was measured using fluorescence-based assays. Apoptotic cells were detected by Hoechst 33342 and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining; protein expression was detected by Western blotting. TGZ inhibited cell proliferation in a dose-dependent manner in both cell lines, and the effect was not suppressed by a PPARγ inhibitor. Additionally, TGZ increased apoptotic cell number and upregulated p38 and c-Jun N-terminal kinase (JNK) phosphorylation; however, p38 and JNK inhibitors did not block TGZ-mediated inhibition of cell proliferation in either cell line. TGZ also upregulated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, whereas an ERK1/2 inhibitor enhanced TGZ-mediated cytotoxicity in A549 cells. Additionally, TGZ increased LC3-II expression, and chloroquine (an autophagy inhibitor) attenuated TGZ-mediated inhibition of cell proliferation. These findings suggest that TGZ-induced inhibition of cell proliferation is PPARγ independent. TGZ-mediated inhibition of cell proliferation was accompanied by apoptosis and independent of the MAPK signaling pathway. These results suggest that TGZ inhibits cell proliferation through autophagy-induced cytotoxicity. This study demonstrated that chemotherapy using TGZ may be effective for lung adenocarcinoma.
Topics: Adenocarcinoma of Lung; Apoptosis; Autophagy; Cell Line; Cell Line, Tumor; Cell Proliferation; Chromans; Humans; Thiazolidinediones; Troglitazone
PubMed: 35228393
DOI: 10.1248/bpb.b21-00785 -
Frontiers in Cell and Developmental... 2021The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular...
The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying this hypoxic disease has not been fully elucidated. Bioinformatics was adopted to screen out the key hypoxia-related genes in PAH. Gain- and loss-function assays were then performed to test the identified hypoxic pathways . Human PAECs were cultured under hypoxic (3% O) or normoxic (21% O) conditions. Hypoxia-induced changes in apoptosis and proliferation were determined by flow cytometry and Ki-67 immunofluorescence staining, respectively. Survival of the hypoxic cells was estimated by cell counting kit-8 assay. Expression alterations of the target hypoxia-related genes, cell cycle regulators, and apoptosis factors were investigated by Western blot. According to the Gene Expression Omnibus dataset (GSE84538), differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ (Dec1-PPARγ) axis was defined as a key hypoxia-related signaling in PAH. A negative correlation was observed between Dec1 and PPARγ expression in patients with hypoxic PAH. observations revealed an increased proliferation and a decreased apoptosis in PAECs under hypoxia. Furthermore, hypoxic PAECs exhibited remarkable upregulation of Dec1 and downregulation of PPARγ. Dec1 was confirmed to be crucial for the imbalance of proliferation and apoptosis in hypoxic PAECs. Furthermore, the pro-surviving effect of hypoxic Dec1 was mediated through PPARγ inhibition. For the first time, Dec1-PPARγ axis was identified as a key determinant hypoxia-modifying signaling that is necessary for the imbalance between proliferation and apoptosis of PAECs. These novel endothelial signal transduction events may offer new diagnostic and therapeutic options for patients with hypoxic PAH.
PubMed: 34765605
DOI: 10.3389/fcell.2021.757168 -
Cell Death & Disease Dec 2022Impairment of liver regeneration leads to severe morbidity in acute and chronic severe liver disease. Transient receptor potential melastain 8 (TRPM8) is involved in a...
Impairment of liver regeneration leads to severe morbidity in acute and chronic severe liver disease. Transient receptor potential melastain 8 (TRPM8) is involved in a variety of processes, including temperature sensing, ion homeostasis, and cell proliferation. However, whether TRPM8 contributes to liver regeneration is still unclear. We assessed the effect and mechanism of TRPM8 in liver regeneration and hepatocyte proliferation in vivo and in vitro. In this study, we found that TRPM8 deficiency impairs liver regeneration in mice. Mechanistically, the results revealed that mitochondrial energy metabolism was attenuated in livers from TRPM8 knockout (KO) mice. Furthermore, we found that TRPM8 contributes to the proliferation of hepatocytes via PGC1α. Taken together, this study shows that TRPM8 contributes to liver regeneration in mice after hepatectomy. Genetic approaches and pharmacological approaches to regulate TRPM8 activity may be beneficial to the promotion of liver regeneration.
Topics: Mice; Animals; Liver Regeneration; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Hepatocytes; Hepatectomy; Liver; Cell Proliferation; Mice, Knockout; Energy Metabolism; Mice, Inbred C57BL; TRPM Cation Channels
PubMed: 36526620
DOI: 10.1038/s41419-022-05475-4 -
Journal of Translational Medicine May 2024Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor...
BACKGROUND
Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se.
METHODS
VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis.
RESULTS
VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis.
CONCLUSIONS
VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.
Topics: Humans; Glioblastoma; Vascular Endothelial Growth Factor Receptor-2; Cell Proliferation; Mitochondria; Cell Line, Tumor; Organelle Biogenesis; Apoptosis; Reactive Oxygen Species; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Brain Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38702818
DOI: 10.1186/s12967-024-05155-1 -
Translational Oncology Jun 2024One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and... (Review)
Review
One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important 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. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.
PubMed: 38917593
DOI: 10.1016/j.tranon.2024.102039 -
Frontiers in Physiology 2022Atherosclerosis is the hallmark of cardiovascular disease (CVD) which is a leading cause of death in type 2 diabetes patients, and glycemic control is not beneficial in... (Review)
Review
Atherosclerosis is the hallmark of cardiovascular disease (CVD) which is a leading cause of death in type 2 diabetes patients, and glycemic control is not beneficial in reducing the potential risk of CVD. Clinically, it was shown that Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are insulin sensitizers with reducing risk of CVD, while the potential adverse effects, such as weight gain, fluid retention, bone loss, and cardiovascular risk, restricts its use in diabetic treatment. PPARγ, a ligand-activated nuclear receptor, has shown to play a crucial role in anti-atherosclerosis by promoting cholesterol efflux, repressing monocytes infiltrating into the vascular intima under endothelial layer, their transformation into macrophages, and inhibiting vascular smooth muscle cells proliferation as well as migration. The selective activation of subsets of PPARγ targets, such as through PPARγ post-translational modification, is thought to improve the safety profile of PPARγ agonists. Here, this review focuses on the significance of PPARγ activity regulation (selective activation and post-translational modification) in the occurrence, development and treatment of atherosclerosis, and further clarifies the value of PPARγ as a safe therapeutic target for anti-atherosclerosis especially in diabetic treatment.
PubMed: 35309069
DOI: 10.3389/fphys.2022.826811 -
Ecotoxicology and Environmental Safety Jun 2022Selenium is an essential micronutrient derived from daily diet to maintain the normal growth and development of vertebrates. Excessive selenium intake will induce...
Selenium is an essential micronutrient derived from daily diet to maintain the normal growth and development of vertebrates. Excessive selenium intake will induce cardiovascular toxicity, reproductive toxicity and neurotoxicity. However, there have been few studies of the toxic effects of selenium on neural development and locomotor behavior. In this study, newly fertilized zebrafish embryos were treated with selenium. As a result, selenium treatment at the concentration of 0.5 µM decreased the moving speed and distance and blunted the touch response of zebrafish embryos. TUNEL assay and immunofluorescence analysis revealed that selenium induced nervous system impairment including promoted cell apoptosis, proliferation and neuroinflammation, and decreased neurons in zebrafish embryos. RNA-seq and RT-PCR results indicated that selenium treatment significantly decreased the expression of the dopaminergic neuron, motor neuron, GABAergic neuron and neurotransmitter transport marker genes in zebrafish embryos. The expression of PPAR signaling pathway marker genes was significantly down-regulated in selenium-treated embryos. Two PPAR agonists (rosiglitazone and bezafibrate) and an anti-cancer drug (cisplatin) were tested for their effects to alleviate selenium-induced locomotor defects. Rosiglitazone and bezafibrate could restore the expression of some neural marker genes but could not fully rescue the selenium-induced locomotor behavior defects. The supplementation of cisplatin could restore the dysfunctional locomotor behavior and the abnormal expression of the PPAR and neural marker genes to almost the normal levels. In conclusion, the results of this study reveal that selenium-induced neural development and locomotor behavior defects are caused by multiple complex factors including PPAR signaling, and all the factors might be recovered by cisplatin through unknown mechanisms.
Topics: Animals; Bezafibrate; Cisplatin; Embryo, Nonmammalian; Peroxisome Proliferator-Activated Receptors; Rosiglitazone; Selenium; Zebrafish
PubMed: 35526456
DOI: 10.1016/j.ecoenv.2022.113611 -
Cells Jan 2022Pex11, an abundant peroxisomal membrane protein (PMP), is required for division of peroxisomes and is robustly imported to peroxisomal membranes. We present a...
Pex11, an abundant peroxisomal membrane protein (PMP), is required for division of peroxisomes and is robustly imported to peroxisomal membranes. We present a comprehensive analysis of how the Pex11 is recognized and chaperoned by Pex19, targeted to peroxisome membranes and inserted therein. We demonstrate that Pex11 contains one Pex19-binding site (Pex19-BS) that is required for Pex11 insertion into peroxisomal membranes by Pex19, but is non-essential for peroxisomal trafficking. We provide extensive mutational analyses regarding the recognition of Pex19-BS in Pex11 by Pex19. Pex11 also has a second, Pex19-independent membrane peroxisome-targeting signal (mPTS) that is preserved among Pex11-family proteins and anchors the human HsPex11γ to the outer leaflet of the peroxisomal membrane. Thus, unlike most PMPs, Pex11 can use two mechanisms of transport to peroxisomes, where only one of them depends on its direct interaction with Pex19, but the other does not. However, Pex19 is necessary for membrane insertion of Pex11. We show that Pex11 can self-interact, using both homo- and/or heterotypic interactions involving its N-terminal helical domains. We demonstrate that Pex19 acts as a chaperone by interacting with the Pex19-BS in Pex11, thereby protecting Pex11 from spontaneous oligomerization that would otherwise cause its aggregation and subsequent degradation.
Topics: Amino Acid Sequence; Cell Proliferation; Humans; Membrane Proteins; Molecular Chaperones
PubMed: 35011719
DOI: 10.3390/cells11010157 -
Open Life Sciences 2023Obesity is a main risk factor for diabetes and cardiovascular disorders and is closely linked to preadipocyte differentiation or adipogenesis. Peroxisome...
Obesity is a main risk factor for diabetes and cardiovascular disorders and is closely linked to preadipocyte differentiation or adipogenesis. Peroxisome proliferator-activated receptor γ (PPARγ) is an indispensable transcription factor in adipogenesis. A newly identified long noncoding RNA, , exerts a protective effect against cardiomyocyte injury by transactivating PPARγ signaling. However, the function of in preadipocyte differentiation is unclear. To investigate the function of in adipogenesis, a well-established preadipocyte, the 3T3-L1 cell line, was induced to differentiate, and level was assessed during differentiation using quantitative real-time PCR. The biological role of in adipogenesis was analyzed by assessing lipid droplet accumulation, PPARγ and CCAAT/enhancer-binding protein α (C/EBPα) expression, and 3T3-L1 cell proliferation and apoptosis after silencing. We found that level was promptly increased during preadipocyte differentiation . was also significantly upregulated in obese mouse-derived subcutaneous, perirenal, and epididymal fat tissues compared with nonobese mouse-derived adipose tissues. Functionally, depletion inhibited preadipocyte differentiation, as evidenced by a significant decrease in lipid accumulation and PPARγ and C/EBPα expression levels. silencing also inhibited 3T3-L1 cell proliferation, whereas overexpression accelerated 3T3-L1 cell proliferation and decreased cell apoptosis. Taken together, the current results reveal a novel function of in regulating preadipocyte proliferation and differentiation.
PubMed: 36820208
DOI: 10.1515/biol-2022-0552 -
Translational Cancer Research Jul 2022Peroxisome proliferator-activated receptor gamma (PPARG) plays some roles in preventing liver disease progression to hepatocellular carcinoma. However, there is limited...
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPARG) plays some roles in preventing liver disease progression to hepatocellular carcinoma. However, there is limited information about the function of PPARG of in hepatocellular carcinoma. This study aimed to determine the significance of PPARG in immunological response and as a biomarker for hepatocellular carcinoma survival.
METHODS
We investigated the expression, prognosis, Kyoto Encyclopedia of Genes and Genomes/Gene Ontology biological process enrichment, and immune significance of PPARG using data from three databases-The Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus-through bioinformatics analysis as well as experimental verification in proliferation function of PPARG in HepG2 cell.
RESULTS
High PPARG expression in hepatocellular carcinoma tissues positively correlated with mutation, and predicted poor prognosis. The results of enrichment and immune infiltration showed that PPARG negatively correlated with the complement system and macrophage infiltration, and laboratory results support that PPARG regulate proliferation of HepG2 cell.
CONCLUSIONS
PPARG is upregulated in hepatocellular carcinoma and it correlates with a worse prognosis. Moreover, PPARG may play an important role in the cell proliferation, complement system and immune cell infiltration in hepatocellular carcinoma.
PubMed: 36249888
DOI: 10.21037/tcr-21-2853