Figure 3 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Effect of GL-V9 on CRC cell invasion and adhesion in vitro. (A-B) CRC cells HCT116 and SW480 treated with 10 μM and 20 μM GL-V9 for 24 h demonstrated significantly reduced migration and invasion through extracellular matrix as indicated by the transwell migration assay. Normal colon epithelial cells FHC with much lower invasive potential also showed reduced invasion through the extracellular matrix (ECM) after GL-V9 treatment, but with less reduction degree and statistical significance. The number of cells migrated through the ECM after 24 h was counted in five randomly selected (×200) microscopic fields. (C) GL-V9 treatment for 24 h at a concentration of 20 μM significantly reduced cell adhesion for both CRC cells HCT116 and SW480 and normal cells FHC, as indicated by cell attachment assay. Each error bar represents the mean ± S.D. of three replicate samples. * p<0.05; **, p<0.001.
Source publication
Tumor distant metastasis is the primary cause of death in colorectal cancer (CRC) patients. GL-V9 is a newly synthesized flavonoid derivative with several beneficial biological functions including anti-tumor and anti-inflammation. However, the anti-metastatic effect of GL-V9 and related mechanisms in CRC remains unknown. In this study, the anti-inv...
Contexts in source publication
Context 1
... were (9.50 ± 2.59)% and (10.50 ± 3.30)% for HCT116 and SW480 cells treated with 20 μM of GL-V9, but were (79.67 ± 5.61)% and (83.83±4.49)% for HCT116 and SW480 cells without GL-V9 treatment (Fig. 2). In addition, transwell migration assay indicated that GL-V9 treatment led to remarkable decrease in the invasive capacities of CRC cells (p < 0.001; Fig. 3A, B). Compared with CRC cells, normal colon cells exhibited much lower migratory property. The extent of wound closure was only (0.038 ± 0.02)% for FHC cells without GL-V9 treatment and was (0.004 ± 0.01)% for FHC cells treated with 20 μM of GL-V9 (p=0.003; Fig. 2). Similarly, the invasive capacity of FHC cells was much lower than that of ...
Context 2
... and was (0.004 ± 0.01)% for FHC cells treated with 20 μM of GL-V9 (p=0.003; Fig. 2). Similarly, the invasive capacity of FHC cells was much lower than that of CRC cells. The number of FHC cells migrated through the extracellular matrix (ECM) was 11.83 ± 2.32 without GL-V9 treatment, but was only 6.5 ± 2.74 after treatment of 20 μM GL-V9 (p=0.005; Fig. 3A, ...
Context 3
... components. Here we also examined the effect of GL-V9 on cell adhesion using the cell attachment assay. GL-V9 treatment significantly reduced CRC cell adhesion as compare with the control group (p<0.001). At a concentration of 20 μM, the inhibitory rates of cell adhesion were (56.63 ± 9.83)% for HCT116 cells and (48.97 ± 3.35)% for SW480 cells (Fig. 3C). For FHC cells, treatment of 20 μM GL-V9 also significantly reduced cell adhesion (p=0.005), but the inhibitory rates was only (14.02 ± 5.57)% (Fig. 3C). Collectively, our results demonstrated that GL-V9 significantly reduced CRC cell migration, invasion, and adhesion in a dose-dependent ...
Context 4
... adhesion as compare with the control group (p<0.001). At a concentration of 20 μM, the inhibitory rates of cell adhesion were (56.63 ± 9.83)% for HCT116 cells and (48.97 ± 3.35)% for SW480 cells (Fig. 3C). For FHC cells, treatment of 20 μM GL-V9 also significantly reduced cell adhesion (p=0.005), but the inhibitory rates was only (14.02 ± 5.57)% (Fig. 3C). Collectively, our results demonstrated that GL-V9 significantly reduced CRC cell migration, invasion, and adhesion in a dose-dependent ...
Similar publications
PLA2R1 is a novel gene that is aberrantly expressed in a variety of malignancies. However, the role and mechanism of PLA2R1 in thyroid cancer has not been elucidated. We aimed to uncover the underlying mechanism of PLA2R1 in thyroid cancer. We collected 115 clinical specimens, including 54 tumor tissues and 61 para-cancerous tissues, who underwent...
Bladder carcinoma (BC) is the tenth most frequent malignancy worldwide, with high morbidity and mortality rates. Despite recent treatment advances, high-grade BC and muscle-invasive BC present with significant progression and recurrence rates, urging the need for alternative treatments. The microRNA-21 (miR-21) has superexpression in many malignanc...
- [...]
Background
Cancer of the bladder (BCa) is one of the most common cancer of the urinary system.Colony-stimulating factor 2 (CSF2) was involved in lots of cancers, but BCa. We examined the effect of CSF2 on BCa in this study and the underlying molecular mechanisms.
Materials and methods
CSF2 mRNA levels in BCa were analyzed using the Cancer Genome A...
Background: Pyruvate kinase M2 (PKM2) is conducive to tumor formation and progression for several types of cancer. Its role in the tumorigenesis and progress of cutaneous squamous cell carcinoma (CSCC) remains unknown. We sought to explore the expression and function of PKM2 in CSCC.
Methods: The expression of PKM2 in 62 cases of actinic keratoses...
Background:
Alopecia has become an exceedingly prevalent dermatological disorder. Etiologically, infection (bacterial and fungal infection), inflammation, and immune dysregulation are the main causes of immune-mediated hair loss. Treating hair loss has remained challenging as the available therapies are limited. Exosomes from adipose-derived stem...
Citations
... Western blotting was carried out as previously described [6]. The total protein in HCC cells was extracted using Radio immunoprecipitation assay (RIPA) buffer(Beyotime, China). ...
Distant metastasis and post-operative recurrence of tumours are the main causes of death in patients with hepatocellular carcinoma (HCC). In recent years, flavonoids have been found to achieve effective anticancer effects by inhibiting cancer cell proliferation and inducing apoptosis, inhibiting cancer cell invasion and metastasis and neovascularization. GL-V9 is a newly synthesized flavonoid that has been demonstrated anticancer effects in a variety of tumors, but its anticancer effects in HCC and its related mechanisms are still unclear. In this study, we investigated the anti-proliferative, anti-invasive and anti-migratory activities of GL-V9 in HCC cells by MTT method cell proliferation assay, plate cloning assay, transwell invasion assay and cell scratching assay. Based on the results, we found that GL-V9 inhibits the EMT process through a pathway that inhibits Wnt/β-Cantenin pathway signaling, thereby reducing the proliferation, migration and invasion ability of HCC cells. Therefore, GL-V9 may be a novel potential therapeutic agent to inhibit HCC cell metastasis.
... Reduces cell viability, migration, and invasion in a concentration-dependent fashion, Significantly decreased both the protein expression levels and activities of MMP-2 and MMP-9 [109] β-Sitosterol ...
... GL-V9 SW480, SW620, LS174T fashion, Significantly decreased both the protein expression levels and activities of MMP-2 and MMP-9 [109] β-Sitosterol CT-26/luc cells Effectively inhibited metastases, Reduced MMP-9 expression [95] SB202190 HT-29, SW480, SW620 ...
... Moreover, the treatment with GL-V9 significantly decreased both the protein expression levels and activities of MMP-2 and MMP-9. Further investigation into the mechanisms involved showed that GL-V9 obstructs the PI3K/Akt signaling pathway, which is upstream of MMP-2 and MMP-9 [109]. ...
Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment.
... MMPs also regulate apoptosis in cancer and enhance chemoresistance. MMP 2 and MMP 9 activate PI3K/AKT signaling pathway that promote cell survival and inhibit apoptosis of cancer cell (Gu et al., 2021). So, increased expression of MMPs in cancer cells makes them less responsive to chemotherapy. ...
... MMP-2 is centrally involved in cancer invasion and metastasis by influencing ECM remodeling, angiogenesis, lymphangiogenesis, and integrin-cell binding [59]. Downregulation of MMP-2 has been shown to decrease the metastatic potential of various cancer cell types, including lung cancer, glioma, colorectal cancer, nasopharyngeal carcinoma [60][61][62][63]. In our study, we noticed that treating liposarcoma cells with shYAP1-BMSC-CM resulted in impeded migration capacity, concurrently with a reduced MMP-2 protein expression. ...
Introduction:
Liposarcoma constitutes a prevalent subtype of soft tissue sarcoma, represents approximately 20% of all sarcomas. However, conventional chemotherapeutic agents have shown restricted effectiveness in treating liposarcoma patients. Accumulating evidence indicates that mesenchymal stem cells (MSCs) have the characteristic of migration to tumor site, promote or suppress tumors. How human bone marrow mesenchymal stem cells (BMSCs) contribute to liposarcoma phenotype remains poorly understood. This study aims to investigate the effects of human bone marrow mesenchymal stem cell-conditioned medium (BMSC-CM) on the proliferation and migration of liposarcoma cell lines 93T449 and SW872, as well as explore potential underlying mechanisms of BMSC-CM action on these cells.
Materials and methods:
We transfected BMSCs with lentiviral constructs to knock down the transcriptional co-activator Yes-associated protein 1 (YAP1), conditioned medium (CM) obtained from BMSCs and shYAP1-BMSC, respectively. Liposarcoma cell lines 93T449 and SW872 were co-cultured with BMSC-CM or shYAP1-BMSC-CM. Cell proliferation ability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was evaluated using flow cytometric assay. A wound healing assay was used to analyze cell migration. The expression levels of YAP1, Bcl-2, and matrix metalloproteinase-2 (MMP-2) were determined by western blot assay.
Results:
Co-culturing liposarcoma cell lines 93T449 and SW872 with BMSC-CM promoted tumor cell proliferation, while shYAP1-BMSC-CM significantly inhibited cell viability and migration, induced apoptosis, and downregulated Bcl-2 and MMP-2 expression.
Conclusions:
These findings provide new insights into the impact of BMSC-CM on liposarcoma and suggest its possible involvement in liposarcoma cell growth.
... Previous studies show that GL-V9 suppresses invasion and migration of human colorectal cancer cells by inhibiting PI3K/ AKT and MMP-2/9 signaling [35], and inhibits the anchorageindependent growth of breast cancer cells [36]. Treatment with GL-V9 in the absence of proliferation inhibitory concentrations in MHCC-97H and HCC-LM3 cells (Fig. 3D and Supplementary Fig. S4A, B), significantly reduced the migration and invasion (Fig. 4A-C), and the phosphorylation of AMPK, MLC and ROCK1 protein (Fig. 4D). ...
... In our studies, TRPV4 inhibitor GL-V9 exerts strong anti-metastatic efficiency in HCC by inactivating both AMPK and AKT-related pathway. Many previous studies have also demonstrated that GL-V9 inactivates AKT signal in types of cancer [35,[78][79][80]. Similar to the pharmacological components extracted from Scutellaria baicalensis [81,82], GL-V9 achieves the anticancer effects by regulating multiple pathways. ...
Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.
... In addition, the previous study reported that GL-V9 played several important roles in anti-cancer effect. Research had shown that GL-V9 could affect PI3K/Ak and MMP-2/ 9 axis to suppress CRC cell migration and invasion [4], disrupt mitochondrial binding of HKII and induce apoptosis and reduced glycosylation in breast cancer cells [5], eliminate drug-induced senescent MEFs (Mouse embryonic fibroblasts) and senescent breast cancer cells [6], upregulate expression of Trx-1 through activation of the AMPK/FOXO3a pathway and ameliorate the effect of DSS-induced colitis on oxidative stress [7], induces p53 associated senescence and catastrophic mitosis in malignant T cells at sublethal doses [8] and inhibits the expression and nuclear translocation of Trx-1, followed by inhibition of the DNA binding activity of HIF-1α, by suppressing the Trx-1/Ref-1 axis [9], i.e. GL-V9 exhibited extensive anti-tumour mechanisms, including anti-tumor immunity, redox metabolism, cell proliferation, autophagy, apoptosis, cell cycle, and so on. ...
GL-V9, a new synthetic flavonoid derived from wogonin, has shown beneficial biological functions. In this study, accurate and sensitive UPLC–MS/MS methods were developed and validated for the quantification of GL-V9 and its glucuronide metabolite (5-O-glucuronide GL-V9) in Beagle dog plasma. The chromatographic separation was performed on a C8 column (ACE Excel 5 C8 50×3.0 mm) using 0.1% formic acid and acetonitrile were used as mobile phase. Mass detection was performed on a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) interface operating in positive ion mode. Quantitative analysis was performed in multiple reaction monitoring (MRM) mode with the transitions of m/z 410.2→126.1 for GL-V9, m/z 586.3→410.0 for 5-O-glucuronide GL-V9 and m/z 180.0→110.3 for phenacetin (internal standard), respectively. The calibration curves for GL-V9 and 5-O-glucuronide GL-V9 showed excellent linearity over the concentration range of 0.5–500 ng/mL with correlation coefficient greater than 0.99. The intra- and inter-day accuracies were within 99.86% to 109.20% for GL-V9 and 92.55% to 106.20% for 5-O-glucuronide GL-V9, respectively. The mean recovery was 88.64% ± 2.70% for GL-V9, and 92.31% ± 6.28% for 5-O-glucuronide GL-V9, respectively. The validated method was successfully applied to the pharmacokinetic study in Beagle dogs after oral and intravenous administration. The oral bioavailability of GL-V9 was approximately 2.47%~4.35% in Beagle dogs and reached steady state on the fifth day after repeated dosing.
... To study the role of quercetin in PCa cells, PC-3 cells were treated with 50 μmol/L, 100 μmol/L, or 150 μmol/L quercetin for 24 hours, 48 hours, and 72 hours, respectively. To further investigate whether the PI3K/Akt pathway was involved in the effect of quercetin on PCa cells, PC-3 cells were pretreated with 150 μmol/L quercetin for 72 hours and exposed to 20 ng/mL PI3K/Akt signaling activator insulin-like growth factor-1 (IGF-1, Beyotime Biotechnology) for 2 hours [30]. 3 Andrologia 3 cells were injected at a density of 5 × 10 3 cells/well in 96well plates with 100 μL each well. ...
Background. Fuzheng Yiliu decoction (FZYLD) was a traditional prescription with an antitumor effect. We aimed to explore the antitumor effect of FZYLD and its active ingredient, quercetin, on prostate cancer (PCa). Methods. The effective components and potential targets of FZYLD were obtained from the TCMSP, Herb, and Batman databases. The relationship between the active compounds of FZYLD and PCa’s potential targets or pathways was analyzed by Cytoscape 3.8.0 software and the String database. The compound composition of FZYLD was detected by HPLC. The effects of quercetin, with the most effective active ingredient of FZYLD, on PC-3 cell growth, metastasis, and PI3K/AKT pathway were seen by CCK-8 Kit, transwell experiment, TUNEL assay, nude mouse tumorigenesis test, and Western blot analysis. Results. Through network pharmacological analysis, we screened 195 effective active components of FZYLD, covering 290 targets, of which 198 were related to PCa. Quercetin, luteolin, kaempferol, anhydroicaritin, and 7-O-methylismucronulatol were important active compounds. MAPK1, AKT1, MAPK3, STAT3, and Jun were common targets of PCa and FZYLD. Our in vivo and in vitro experimental results confirmed that quercetin inhibited PCa’s growth, cell migration, and the PI3K/AKT pathway and promoted cell apoptosis. Conclusions. As predicted by the network pharmacological strategy and verified by the basic experimental results, FZYLD might play an antitumor role through multiple components, targets, and pathways. These results provide a new basis for developing and applying FZYLD and its compound quercetin.
... Due to their high binding afnity to enzymes [16], favonoids have demonstrated a wide range of pharmacological behaviors in medicine, including anticancer, antioxidant, antiinfammatory, antiallergic, antibacterial, and antiviral properties [17,18]. Tere is growing evidence suggesting the curative potential of favonoids in diferent cancers such as breast [19], colorectal [20], oral [21], and lung cancers [22], as well as hepatocellular carcinoma [19]. ...
Background:
Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer.
Objectives:
The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy.
Methods:
A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor's active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations.
Results:
Kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor's active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations.
Conclusion:
The present study suggests that kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.
... Activation of the PI3/Akt signaling pathway also plays an important role in the regulation of matrix metalloproteinases (MMPs); in particular, MMP-9 has been seen to be regulated by Akt [34,35]. Data presented in this work suggest a correlation between the significant reduction of the Akt signal and the reduction of MMP-9 when EcAII is administered to irradiated samples. ...
Colorectal cancer (CRC) is the most prominent form of colon cancer for both incidence (38.7 per 100,000 people) and mortality (13.9 per 100,000 people). CRC’s poor response to standard therapies is linked to its high heterogeneity and complex genetic background. Dysregulation or depletion of the tumor suppressor p53 is involved in CRC transformation and its capability to escape therapy, with p53null cancer subtypes known, in fact, to have a poor prognosis. In such a context, new therapeutic approaches aimed at reducing CRC proliferation must be investigated. In clinical practice, CRC chemotherapy is often combined with radiation therapy with the aim of blocking the expansion of the tumor mass or removing residual cancer cells, though contemporary targeting of amino acid metabolism has not yet been explored. In the present study, we used the p53null Caco-2 model cell line to evaluate the effect of a possible combination of radiation and L-Asparaginase (L-ASNase), a protein drug that blocks cancer proliferation by impairing asparagine and glutamine extracellular supply. When L-ASNase was administered immediately after IR, we observed a reduced proliferative capability, a delay in DNA-damage response and a reduced capability to adhere and migrate. Our data suggest that a correctly timed combination of X-rays and L-ASNase treatment could represent an advantage in CRC therapy.
... Colony-formation assays showed that sh-CREB1 significantly decreased the number of colonies ( Figure 4B shown that activation of PI3K/Akt promotes cancer cell invasion and metastasis via up-regulating MMP-2 or MMP-9 expression. 15 Next, we F I G U R E 2 miR-450a inhibits T47D and BT474 cell migration and invasion. (A,B) The migration abilities of miR-450a mimic transfected T47D, and BT474 cells were detected by a transwell migration assay. ...
Emerging evidence greatly implicates that microRNA‐450a (miR‐450a) plays an essential role in cancer pathobiology. While the pathological role of miR‐450a in breast carcinogenesis remains enigmatic. Herein, we showed that miR‐450a was lowly expressed in breast cancer cell lines compared with normal, and low miR‐450a expression was associated with poor survival in patients with breast cancer. We revealed that miR‐450a mimic transfected breast cancer cells (T47D and BT474) exhibited attenuated capacities of proliferation, migration, and invasion in vitro, and miR‐450a suppressed T47D cell growth in a xenograft tumor model. Mechanistically, cAMP response element‐binding protein 1 (CREB1) was negatively targeted by miR‐450a, and CREB1 deletion mimicked the effects of miR‐450a mimic treatment. Bioinformatics analysis further revealed that elevated expression of CREB1 correlated with poor prognosis in patients with breast cancer and miR‐450a level was negatively correlated with CREB1 level in breast cancer. Additionally, miR‐450a inhibited the phosphorylation of phosphatidylinositol 3‐kinase/V‐akt murine thymoma viral oncogene homolog (PI3K/AKT) and the activities of matrix metalloproteinase‐2/9 (MMP‐2/9). The following rescue assay indicated that CREB1 was implicated in the anti‐tumoral effect of mR‐450a in breast carcinoma. All these observations disclosed that miR‐450a negatively regulates the growth and metastatic property of breast carcinoma cells.
