Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A.
Ontology highlight
ABSTRACT:
SUBMITTER: Kong R
PROVIDER: S-EPMC8075693 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Ellagic acid (EA) is a polyphenol found in several fruits and plants. EA has been reported to exert antitumor activity in many types of cancers. However, the effect and potential molecular mechanism of EA in endometrial cancer are still unclear. Therefore, the aim of this study was to explore the underlying antitumor function and targets by which EA inhibits endometrial cancer. By using multiplatform bioinformatics analysis tools, including DrugBank, STRING, WebGestalt and cBioPortal, the core targets of EA were identified as PIK3CA and PIK3R1. In addition, through transwell assays, EA was strongly found to inhibit cell invasion and migration. Based on CCK8 assays and flow cytometry, EA exhibited a suppressive effect on endometrial cancer cell proliferation by causing cell cycle arrest and inducing apoptosis. The results of real-time PCR confirmed that the expression of PIK3CA and PIK3R was decreased by EA. Furthermore, western blotting analysis demonstrated that EA inhibited PI3K phosphorylation, downregulating the expression of MMP9. In vivo, EA suppressed lung metastasis in BALB/c nude mice based on the SUVmax value determined from PET scans and HE staining. According to all these data, it comprehensively demonstrated the inhibitory effect of EA on endometrial cancer through bioinformatics analysis and experimental verification. Our findings suggest that EA may potentially be beneficial for treating endometrial cancer.
| S-EPMC6603400 | biostudies-literature
Project description:Background & aimsMany genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis.MethodsColon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry.ResultsLevels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues.ConclusionsLoss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.
| S-EPMC7388731 | biostudies-literature
Project description:The use of molecular-targeted drugs in the treatment of gastric cancer is increasing. However, the variety of molecular-targeted drugs in gastric cancer is still limited, and the development of new molecular-targeted therapies is required. The effect of combining sunitinib (SUN) with pterostilbene (PTE) on the human gastric cancer cell lines TMK1 and MKN74 was examined in in vitro and in vivo. Compared with SUN or PTE treatment alone, cotreatment induced pronounced suppression of cell proliferation, with a marked increase in oxidative stress. SUN was associated with a significant retention of mitochondrial Fe2+. SUN-treated cells decreased expression of PDZ domain-containing protein 8 (PDZD8). Knockdown of PDZD8 in both cells induced Fe2+ retention, and siPDZD8+PTE markedly suppressed cell proliferation with suppressed oxidative phosphorylation, as did the combination of SUN+PTE. In a nude mouse tumor model, a pronounced antitumor effect was observed with SUN+PTE treatment compared to SUN alone. PDZD8 may be a newly discovered off-target for SUN, and that the combined use of PTE with SUN significantly promotes antitumor activity in gastric cancer cell lines. The combined use of SUN and PTE might be a new molecular-targeted therapy for gastric cancer.
| S-EPMC8999764 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer.MethodsVCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography.ResultsVCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption.ConclusionsVCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma.Trial registration numberEudraCT number: 2012-005556-42 and NCT02045589.
| S-EPMC8578996 | biostudies-literature
Project description:Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 μM) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 μM) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G1-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.
| S-EPMC7921121 | biostudies-literature
Project description:Bruceine A (BA), a quassic ester from bruceine javanica, regulates diverse intracellular signal transduction pathways and manifests a variety of biological activities, however, its pharmacological mechanism in treating colon cancer (CC) is unclear. In this study, we investigated the anticancer effects of BA on CC cells and the underlying mechanisms. The network pharmacology research indicated that Akt1 and Jun and PI3K/Akt pathways are the predominant targets and critical signaling pathways, respectively, for BA treatment of CC. Meanwhile, molecular docking results implied that BA could conjugate to pivotal proteins in the PI3K/Akt pathway. BA remarkably suppressed the proliferation of CC cells HCT116 and CT26 with 48-h IC50 of 26.12 and 229.26 nM, respectively, and the expression of p-PI3K/p-Akt was restrained by BA at the molecular level as verified by Western blot assay. Further mechanistic studies revealed BA impacted cell cycle-related proteins by regulating the expression of P27 (a protein bridging the PI3K/Akt signaling pathway with cycle-related proteins), arresting the cell cycle in the G2 phase, inhibiting the proliferation of HCT116 and CT26, and facilitated the apoptosis in CC cells by activating the mitochondria-associated apoptosis protein Bax and accumulating reactive oxygen species, in addition to BA apparently inhibited the migration of CC cells. Taken together, our results demonstrated that BA might be a promising chemotherapy drug in the treatment of CC.
| S-EPMC10086190 | biostudies-literature
Project description:The adipokine chemerin has been considered an important regulator of tumor immune surveillance. Chemerin recruits leukocytes through the receptor CMKLR1 to improve clinical outcomes of tumors and overall patient survival, but the role of GPR1 in tumors has not been widely investigated. Here, we found that GPR1 expression is elevated in breast cancer-especially triple-negative breast cancer (TNBC) tissues and cell lines. Herein, we screened a phage display peptide library to identify LRH7-G5, a peptide antagonist that blocks chemerin/GPR1 signaling. This peptide performed as an anticancer agent to suppress the proliferation of the TNBC cell lines MDA-MB-231 and HCC1937 but has little effect on T47D cells. LRH7-G5 treatment significantly blocked tumor growth in a TNBC cell-bearing orthotopic mouse model. Last, our results showed that this peptide's antitumor role is mediated through the PI3K/AKT signaling pathway. In conclusion, these data collectively suggest that the chemerin receptor GPR1 is a novel target for controlling TNBC progression and establish peptide LRH7-G5 as a new therapeutic agent for suppressing TNBC tumor growth.
| S-EPMC7508919 | biostudies-literature
Project description:Primary liver tumors are mainly represented by hepatocellular carcinoma (HCC), one of the most aggressive and resistant forms of cancer. Liver tumorigenesis is characterized by an accumulation of epigenetic abnormalities, leading to gene extinction and loss of hepatocyte differentiation. The aim of this work was to investigate the feasibility of converting liver cancer cells toward a less aggressive and differentiated phenotype using a process called epigenetic reconditioning. Here, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine (5-AZA) promoted an anti-cancer response by inhibiting HCC cell tumorigenicity. Furthermore, epigenetic reconditioning improved sorafenib response. Remarkably, epigenetic treatment was associated with a significant restoration of differentiation, as attested by the increased expression of characteristic hepatocyte markers in reconditioned cells. In particular, we showed that reexpression of these epigenetically silenced liver genes following 5-AZA treatment or after knockdown of DNA methyltransferase 1 (DNMT1) was the result of regional CpG demethylation. Lastly, we confirmed the efficacy of HCC differentiation therapy by epigenetic reconditioning using an in vivo tumor growth model. In summary, this work demonstrates that epigenetic reconditioning using the demethylating compound 5-AZA shows therapeutic significance for liver cancer and is potentially attractive for the treatment of solid tumors.
| S-EPMC6035736 | biostudies-literature
Project description:Calgranulin B is a small, calcium-binding protein expressed in neutrophils that is secreted into the tumor microenvironment in cancer cases. We previously showed that calgranulin B levels are increased in the stools of colorectal cancer patients. In patient tumor tissues, calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines. Cell lines did not express calgranulin B, but in vitro studies showed that colon cancer cells internalized extracellular calgranulin B, while other types of cancer cells did not. Calgranulin B internalization led to reduced cell proliferation and increased apoptotic cell death. AKT and ERK signals were also increased after calgranulin B treatment, as were p53, ?-catenin, E-cadherin and cleaved caspase-3 levels. Additionally, a human protein microarray identified aurora A kinase as a calgranulin B binding partner, and binding inhibited aurora A kinase activity in a dose-dependent manner. Our findings demonstrate the antitumor effects of calgranulin B in the inflammatory microenvironment and suggest that calgranulin B could be potentially efficacious in the treatment of colon cancer.
| S-EPMC4991461 | biostudies-literature
Project description:BackgroundBreast cancer is one of the leading causes of cancer-related morbidities. The present study aimed to evaluate the efficacy of bithiophene-fluorobenzamidine (BFB) against breast cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) in female Swiss mice and reveal the underlining mechanisms.MethodsThe mice were randomly divided into five groups; control, BFB-treated group, DMBA-treated group, and the last two groups received DMBA then tamoxifen or BFB.ResultsBFB reduced the tumor incidence by ~ 88% versus 30% after TAM. DMBA significantly increased the expression of CDK1 and HER2 and reduced the expression of p53, p21 (CDKN1A), ESR-α, and CAS3. BFB caused significant down-regulation of CDK1 and HER2 and upregulation of p53, p21, ESR-α, and CAS3. In the DMBA-treated mice, cancerous cells metastasized to several organs. This was prevented by the administration of BFB. The antimetastatic and proapoptotic activities were confirmed in MCF7 cells in vitro by the wound healing and annexin V assays, respectively. Kaplan-Meier analysis showed that the BFB increased survival. In the DMBA group, tumors showed invasive carcinoma of grade III with central necrosis, polymorphism, mitotic activity, and numerous newly formed ductules, and colloidal mucinous secretions within adenoid cysts. BFB administration restored the normal structure of the mammary glands.ConclusionTaken together, BFB has antitumor, pro-apoptotic, and anti-metastatic activities against breast cancer in mice and therefore, it merits further investigations.
| S-EPMC9478011 | biostudies-literature