scholarly journals Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer through Mediation of the LIFR/STATs Axis

2020 ◽  
Author(s):  
Dandan Zheng ◽  
Yu Zhu ◽  
Youqun Xiang ◽  
Xuanxuan Dai ◽  
Wanle Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blotting ◽  
Cell Function ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Leukemia Inhibitory Factor Receptor ◽  
Antitumor Effects

Abstract Background: Colorectal cancer (CRC) is the second deadliest malignant disease in the world, with a large number of new cases being reported every year. The leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC. The inactivation of STATs is a promising anticancer strategy. Cynaropicrin is a sesquiterpene lactone with a variety of pharmacological functions, which may be used as a potential targeted cancer drug for the prevention or treatment of human CRC. Methods: Cell function tests were performed to observe the inhibitory effect of Cynaropicrin on human CRC cells (RKO, HCT116 and DLD1). Expression levels of LIFR, P-STAT3, P-STAT4 and apoptotic proteins were detected by Western blotting. Immunoprecipitation confirmed the presence of LIFR/STAT3/STAT4 complex. Cell immunofluorescence assay was used to observe the subcellular localization of STAT3 and STAT4. In vivo efficacy of Cynaropicrin was evaluated by a xenotransplantation model in nude mice.Results: Cynaropicrin significantly reduced the survival ability of human CRC cells and promoted apoptosis in a dose-dependent manner. Western blotting results suggested that the antitumor effects of cynaropicrin might be mediated by inhibition of the LIFR/STATs axis. Cynaropicrin reduced the formation of STAT3/STAT4 heterodimers and blocked their entry into the nucleus. Cynaropicrin also suppressed tumor growth in the HCT116 xenograft model.Conclusion: The above experimental results showed that cynaropicrin exerted a strong inhibitory effect on CRC in vitro and in vivo. Our study concluded that cynaropicrin has potential application prospects in the field of anti-CRC therapy.

scholarly journals Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer Through Mediation of the LIFR/STATs Axis

2021 ◽  
Vol 8 ◽  
Author(s):  
Dandan Zheng ◽  
Yu Zhu ◽  
Yili Shen ◽  
Sisi Xiao ◽  
Lehe Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blotting ◽  
Cell Function ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Leukemia Inhibitory Factor Receptor ◽  
Antitumor Effects

BackgroundColorectal cancer (CRC) is the second deadliest malignant disease in the world and the leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC.MethodsCell function tests were performed to observe the inhibitory effect of cynaropicrin on human CRC cells (RKO, HCT116, and DLD-1). Expression levels of LIFR, P-STAT3, P-STAT4, and apoptotic proteins were detected by Western blotting. Immunoprecipitation confirmed the presence of LIFR/STAT3/STAT4 complex. Cell immunofluorescence assay was used to observe the subcellular localization of STAT3 and STAT4. In vivo efficacy of cynaropicrin was evaluated by a xenotransplantation model in nude mice.ResultsCynaropicrin significantly reduced the survival ability of human CRC cells and promoted apoptosis in a dose-dependent manner. Western blotting results suggested that the antitumor effects of cynaropicrin might be mediated by inhibition of the LIFR/STATs axis. Cynaropicrin reduced the formation of STAT3/STAT4 heterodimers and blocked their entry into the nucleus. Cynaropicrin also suppressed tumor growth in the xenograft model.ConclusionThe results showed that cynaropicrin exerted a strong inhibitory effect on CRC in vitro and in vivo. Our study concluded that cynaropicrin has potential application prospects in the field of anti-CRC therapy.

scholarly journals Antitumor Effects of MRS5698, a Cordycepin Derivative, on Endometrial Cancer Cells

2019 ◽  
Vol 14 (10) ◽  
pp. 1934578X1988156
Author(s):  
Pedro Fong ◽  
Cheng-I Loi ◽  
Wan-Fong U ◽  
Chou-I Choi ◽  
Tao Yi ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Inhibitory Effect ◽  
Antagonistic Effect ◽  
Cordyceps Sinensis ◽  
New Drugs ◽  
Cancer Drug ◽  
Antitumor Effects ◽  
Combined Use ◽  
Ishikawa Cells

Endometrial cancer drug treatments often produce undesirable effects. Thus, discovering new drugs with fewer side effects is required. Cordycepin is a constituent of Cordyceps sinensis, which has been proven to inhibit tumor growth by stimulating the adenosine A3 receptor (A3R). However, cordycepin is rapidly degraded by adenosine deaminase (ADA) and has a clinically unacceptable short half-life. One of its derivatives, MRS5698, was predicted to exhibit antitumor effects with a poor affinity to ADA by our previous validated in silico experiments. The purpose of this study was to explore the possibilities of using MRS5698 as a novel antitumor agent through experiments on Ishikawa and HEC-1A cells. The detection of inhibition and apoptotic rate of MRS5698 and cisplatin, and their combination, on Ishikawa and HEC-1A cells were performed by MTT assays and flow cytometry, respectively. The inhibition rates of MRS5698 on Ishikawa and HEC-1A cells were both significantly higher than the control groups ( P < 0.05). MRS5698 produced a higher inhibitory effect on HEC-1A cells than on Ishikawa cells with IC50 values of 20.55 and 27.25 μg/mL, respectively. MRS5698 had a stronger inhibitory effect than cisplatin on HEC-1A cells. The Annexin V-FITC/propidium iodide assays demonstrated that the total rate of apoptosis of MRS5698 on HEC-1A cells was higher than that on Ishikawa cells. The results of MTT assay and cellular apoptosis showed that the combined use of MRS5698 and cisplatin produces dose-independent antagonistic effects. MRS5698 produced antitumor effects on both cell lines, which were better than that of cordycepin. However, the combined use of MRS5698 and cisplatin produced an antagonistic effect. A further in vivo study could be considered for investigating the antitumor effects of either MRS5698 monotherapy or MRS5698 in combination with other nonplatinum-based chemotherapeutic drugs in treating endometrial cancer.

scholarly journals Ubiquitin-Like Protein UBD Promotes Cell Proliferation in Colorectal Cancer by Facilitating p53 Degradation

2021 ◽  
Vol 11 ◽  
Author(s):  
Hongbin Su ◽  
Mengdi Qin ◽  
Qiang Liu ◽  
Bo Jin ◽  
Xianjun Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blotting ◽  
Xenograft Model ◽  
Proteasome Inhibition ◽  
Tissue Samples ◽  
Functional Changes ◽  
Tumor Tissues ◽  
Expression Plasmids

PurposeUbiquitin D (UBD) is a member of the ubiquitin-like modifier (UBL) family and is highly expressed in a variety of cancers including colorectal cancer (CRC). However, the mechanisms of its regulatory roles in CRC are largely elusive. In this study, we revealed the effect of UBD on the proliferation of CRC.MethodsThe expression of UBD in clinical tissue samples of CRC and seven CRC cell lines was detected using qRT-PCR, immunohistochemistry (IHC) and Western blotting. CCK-8, colony formation, EdU and flow cytometry assays were used to detect the functional changes of CRC cells transfected with UBD stable expression plasmids in vitro. A xenograft model was constructed to assess the effect of UBD on the growth of CRC cells in vivo. The connection between UBD and p53 was analyzed using Western blotting, immunoprecipitation, proteasome inhibition assay and Cycloheximide (CHX) chase assay.ResultsUBD was overexpressed in CRC tumor tissues compared with nontumor tissues, and its overexpression was positively associated with the tumor size and TNM stage of CRC patients. Functionally, UBD significantly accelerated CRC cell viability and proliferation in vitro and promoted tumorigenesis in vivo. Mechanistically, UBD interacted with p53 in CRC cells, downregulated the expression of p53 by regulating its degradation, shortened the p53 half-life, thereby further affecting the decrease in p21 and the increase in Cyclin D1, Cyclin E, CDK2, CDK4 and CDK6. Moreover, in vivo experiments showed that UBD-induced tumor growth in nude mice was dependent on a decrease in p53.ConclusionsOur study proved that UBD mediates the degradation of p53, thereby facilitating the growth of CRC cells and ultimately promoting the progression of CRC. Therefore, UBD may be a potential therapeutic target and a promising prognostic biomarker for CRC.

scholarly journals Genistein Inhibits Human Colorectal Cancer Growth and Suppresses MiR-95, Akt and SGK1

2015 ◽  
Vol 35 (5) ◽  
pp. 2069-2077 ◽  
Author(s):  
Jian Qin ◽  
Jia Xin Chen ◽  
Zhou Zhu ◽  
Jia An Teng
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Protein Levels ◽  
Phosphorylated Akt ◽  
Hct 116 ◽  
Hct 116 Cells

Background: Genistein, a major isoflavonoid isolated from dietary soybean, has been shown to suppress the growth of several cancers through modulation of various pathways. However, the molecular mechanisms by which genistein elicit its effects on colorectal cancer (CRC) cells have not been fully elucidated. In this study, we aimed to investigate the anti-tumor activities of genistein on CRC and its potential mechanism. Methods: Effects of genistein on the cell proliferation were tested in HCT-116 cells by MTT assay, and apoptosis was measured by Flow cytometry. Real-time PCR was also used to evaluate the regulation of genistein on miR-95, Akt and SGK1 expression. The protein levels of total Akt (T-Akt), and phosphorylated Akt (P-Akt) were assessed by western blot. A nude mice xenograft model was employed to determine whether genistein could have an anti-tumor effect on CRC in vivo. Results: We found that treatment of HCT-116 cells with genistein caused an inhibition of cell proliferation and induction of apoptosis. Meanwhile, genistein down-regulated the mRNA expression of Akt, SGK1 and miR-95, and inhibited the phosphorylation of Akt in HCT-116 cells. The experiment in vivo also showed that genistein significantly suppressed the growth of mouse xenograft tumor. Conclusion: This study demonstrates that genistein has an inhibitory effect on CRC involved in reducing miR-95, Akt and SGK1, offering novel insights into the mechanisms of genistein therapeutic actions.

scholarly journals Copanlisib promotes growth inhibition and apoptosis by modulating the AKT/FoxO3a/PUMA axis in colorectal cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Ji Yan ◽  
Shida Yang ◽  
Hong Tian ◽  
Yang Zhang ◽  
Hongmei Zhao
Keyword(s):  
Colorectal Cancer ◽  
Survival Rates ◽  
Xenograft Model ◽  
Caspase Activation ◽  
Anticancer Activities ◽  
Antitumor Effects ◽  
Puma Expression ◽  
Enhanced Expression ◽  
Phosphoinositide 3 Kinase

Abstract Colorectal cancer (CRC) is the type of cancer with the third highest incidence and is associated with high mortality and low 5-year survival rates. We observed that copanlisib, an inhibitor of PI3K (pan-class I phosphoinositide 3-kinase) that preferentially inhibits PI3Kδ and PI3Kα, impedes the growth of CRC cells by inducing apoptosis via PUMA. There was a marked increase in the expression of PUMA independent of p53 after treatment with copanlisib. The response of CRC cells to copanlisib could be predicted by PUMA expression. Copanlisib was found to induce PUMA expression through FoxO3a by directly binding to the PUMA promoter after inhibiting AKT signaling. PUMA deficiency mitigated the apoptosis induced by copanlisib. Caspase activation and mitochondrial dysfunction led to copanlisib resistance, as observed through a clonogenic assay, whereas enhanced expression of PUMA increased the copanlisib-induced susceptibility to apoptosis. Moreover, the antitumor effects of copanlisib were suppressed by a deficiency of PUMA in a xenograft model, and caspase activation and reduced apoptosis were also observed in vivo. Copanlisib-mediated chemosensitization seemed to involve the concurrent induction of PUMA expression via mechanisms that were both dependent and independent of p53. These observations indicate that apoptosis mediated by PUMA is crucial for the anticancer effects of copanlisib and that manipulation of PUMA may aid in enhancing anticancer activities.

scholarly journals The New PI3K/mTOR Inhibitor GNE-477 Inhibits the Malignant Behavior of Human Glioblastoma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Yixuan Wang ◽  
Heng Shen ◽  
Qian Sun ◽  
Linyao Zhao ◽  
Hao Liu ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Central Nervous System Tumor ◽  
Antitumor Effects ◽  
Concentration Dependent Manner ◽  
Induced Apoptosis

The most common primary central nervous system tumor in adults is glioblastoma multiforme (GBM). The high invasiveness of GBM cells is an important factor leading to inevitable tumor recurrence and a poor prognosis of patients. GNE-477, a novel PI3K/mTOR inhibitor, has been reported to exert antiproliferative effects on other cancer cells. However, researchers have not clearly determined whether GNE-477 produces antitumor effects on GBM. In the present study, GNE-477 significantly inhibited the proliferation, migration and invasion of U87 and U251 cells. In addition, GNE-477 also induced apoptosis of GBM cells, arresting the cell cycle in G0/G1 phase. More importantly, GNE-477 also reduced the levels of AKT and mTOR phosphorylation in the AKT/mTOR signaling pathway in a concentration-dependent manner. An increase in AKT activity induced by SC79 rescued the GNE-477-mediated inhibition of GBM cell proliferation and apoptosis. The antitumor effects of GNE-477 and the regulatory effects on related molecules were further confirmed in vivo using a nude mouse intracranial xenograft model. In conclusion, our study indicated that GNE-477 exerted significant antitumor effects on GBM cells in vitro and in vivo by downregulating the AKT/mTOR pathway.

scholarly journals Apigenin Inhibits Histamine-Induced Cervical Cancer Tumor Growth by Regulating Estrogen Receptor Expression

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1960 ◽  
Author(s):  
Erkang Zhang ◽  
Yani Zhang ◽  
Zhuoyan Fan ◽  
Lei Cheng ◽  
Shiwen Han ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Antioxidant Properties ◽  
Xenograft Model ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Antitumor Effects

Apigenin is a natural flavone with anti-inflammatory and antioxidant properties and antitumor abilities against several types of cancers. Previous studies have found that the antitumor effects of apigenin may be due to its similar chemical structure to 17β-estradiol (E2), a main kind of estrogen in women. However, the precise mechanism underlying the antitumor effects of apigenin in cervical cancer remains unknown. On the other hand, there is increasing evidence that describes a histamine role in cancer cell proliferation. In this study, we examined whether apigenin can attenuate the effects of histamine on tumors by regulating the expression level of estrogen receptors (ERs) to inhibit cervical cancer growth. Our in vitro data indicates that apigenin inhibited cell proliferation in a dose-dependent manner in human cervical cancer cells (HeLa), while histamine shows the opposite effects. After that, the xenograft model was established to explore the antitumor effects of apigenin in vivo, the results show that apigenin inhibited cervical tumor growth by reversing the abnormal ER signal in tumor tissue which was caused by histamine. We also demonstrate that apigenin inhibited cell proliferation via suppressing the PI3K/Akt/mTOR signaling pathway. Collectively, our results suggest that apigenin may inhibit tumor growth through the ER-mediated PI3K/Akt/mTOR pathway and that it can also attenuate the effects of histamine on tumors.

scholarly journals Zuo Jin Wan, a Traditional Chinese Herbal Formula, Reverses P-gp-Mediated MDRIn VitroandIn Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Hua Sui ◽  
Xuan Liu ◽  
Bao-Hui Jin ◽  
Shu-Fang Pan ◽  
Li-Hong Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Xenograft Model ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Chemotherapeutic Drugs ◽  
Reversal Effect

Zuo Jin Wan (ZJW), a typical traditional Chinese medicine (TCM) formula, has been identified to have anticancer activity in recent studies. In this study, we determined the underlying mechanism of ZJW in the reversal effect of multidrug resistance on colorectal cancerin vitroandin vivo. Our results showed that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs in HCT116/L-OHP, SGC7901/DDP, and Bel/Fu MDR cells. Moreover, combination of chemotherapy with ZJW could reverse the drug resistance of HCT116/L-OHP cells, increase the sensitivity of HCT116/L-OHP cells to L-OHP, DDP, 5-Fu, and MMCin vitro, and inhibit the tumor growth in the colorectal MDR cancer xenograft model. ICP-MS results showed that ZJW could increase the concentration of chemotherapeutic drugs in HCT116/L-OHP cells in a dose-dependent manner. Furthermore, we showed that ZJW could reverse drug resistance of colorectal cancer cells by decreasing P-gp levelin vitroandin vivo, which has been represented as one of the major mechanisms that contribute to the MDR phenotype. Our study has provided the first direct evidence that ZJW plays an important role in reversing multidrug resistance of human colorectal cancer and may be considered as a useful target for cancer therapy.

scholarly journals Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer

2017 ◽  
Vol 44 (3) ◽  
pp. 1051-1063 ◽  
Author(s):  
Hefei Wang ◽  
Bing Liu ◽  
Jing Wang ◽  
Jinglin Li ◽  
Ying Gong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Downstream Target ◽  
Colorectal Cancer Cells ◽  
Unpaired Student ◽  
Sphere Formation

Background/Aims: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. Methods: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. Results: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. Conclusion: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.

scholarly journals Glucolipotoxicity and GLP-1 secretion

2021 ◽  
Vol 9 (1) ◽  
pp. e001905
Author(s):  
Jung-Hee Hong ◽  
Dae-Hee Kim ◽  
Moon-Kyu Lee
Keyword(s):  
Glucose Transporter ◽  
Cell Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Simultaneous Treatment ◽  
L Cells ◽  
Triglyceride Accumulation

IntroductionThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels.Research design and methodsTo investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function.ResultsChronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats.ConclusionThese results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.

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