Invasion Of Human Cancer Cells Research Articles

Downregulated RRS1 inhibits invasion and metastasis of BT549 through RPL11‑c‑Myc‑SNAIL axis.

Regulator of ribosome synthesis 1 (RRS1) is a key factor in ribosome biosynthesis and other cellular functions. High level of RRS1 in breast cancer cell lines is associated with increased cell proliferation, invasion and migration. RRS1 controls the assembly of the 60s subunit and maturation of 25S rRNA during ribosome biosynthesis. In this study, lentiviral transfection of sh-RNA was used to knock down the level of RRS1, to detect the effect of RRS1 on cell function and to explore the specific mechanism of RRS1 affecting cell invasion and metastasis by COIP and dual-luciferase reporter gene assays. The present study found that RRS1 knockdown reduced the accumulation of ribosome protein L11 (RPL11) in the nucleolus, which then migrated to the nucleoplasm and bound to c-Myc. This inhibited trans-activation of SNAIL by c-Myc and eventually decreased the invasion and metastasis capacity of the human breast cancer cell line BT549. Taken together, RRS1 regulates invasion and metastasis of human breast cancer cells through the RPL11-c-Myc-SNAIL axis. The findings are of great significance for exploring the mechanism of breast cancer invasion and metastasis and the corresponding regulatory factors.

Arctiin Inhibits Cervical Cancer Cell Migration and Invasion through Suppression of S100A4 Expression via PI3K/Akt Pathway.

Arctiin, a lignan glycoside, is isolated from Arctium lappa L. The anticancer effects of arctiin have been demonstrated in several studies. However, no research has been conducted on the anti-migration effect of arctiin in cervical cancer cells. The present study examined the effects of arctiin on cervical cancer cells and investigated the possible molecular mechanism. We demonstrated that arctiin exhibited low cytotoxicity and significantly inhibited cell migration and invasion in human cervical cancer cells. The S100A4 protein expression and mRNA levels were significantly reduced in HeLa and SiHa cells with arctiin treatment. Furthermore, silencing S100A4 by using small interfering RNA reduced cell migration, while overexpression of S100A4 mitigated the migration inhibition imposed by arctiin in cervical cancer cells. Western blotting revealed that arctiin significantly reduced phosphoinositide 3-kinase (PI3K) and phosphorylation of Akt in cervical cancer cells. Moreover, selective Akt induction by an Akt activator, SC-79, reverted cervical cancer cell migration and S100A4 protein expression, which were reduced in response to arctiin. Taken together, these results suggest that arctiin inhibits cervical cancer cell migration and invasion through suppression of S100A4 and the PI3K/Akt pathway.

HPV16 E6 promotes cell proliferation, migration, and invasion of human cervical cancer cells by elevating both EMT and stemness characteristics.

In most cases of cervical cancer, the high risk of the disease is caused by the human papilloma virus (HPV). Surgery or radiation usually benefits patients with early cervical cancer, while the metastatic one is uncurable and new therapeutic strategies and approaches are required. In this study, HPV16 E6 silence or overexpression were carried out to evaluate the possible mechanisms of HPV16 E6 function in cervical cancer cells with different HPV16 E6 expression background. HPV16 E6-positive cervical cancer cell Siha exerts significantly stronger cell invasion and migration potentials than the HPV16 E6-negative C33A cells. HPV16 E6 silence significantly weakened the potentials of cell invasion and migration, cell proliferation and stemness characteristic in Siha cells. Meanwhile, the overexpression of HPV16 E6 effectively promoted the cell proliferation and stemness characteristic in C33A cells. Our data also indicated a positive association between HPV16 E6 and the levels of epithelial to mesenchymal transition (EMT), and cell stemness. The ectopic expression of OCT4 could effectively reverse the inhibitory roles of HPV16 E6 silence on cell migration, invasion, and stemness in Siha cells. More interestingly, we found that HPV16 E6 might promote the OCT4 expression by impairing the direct binding of p53 on the promoter and activate its transcription. Taken together, our results indicated that HPV16 E6 could promoted the potential cell proliferation, migration, and invasion of human cervical cancer cells by modulating EMT and cell stemness. Our data provide a novel mechanism for how HPV16 E6 acts as a key risk factor for cervical cancer development and progression.

TDG suppresses the migration and invasion of human colon cancer cells via the DNMT3A/TIMP2 axis.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors with high rates of recurrence and mortality. Thymine DNA glycosylase (TDG) is a key molecule in the base excision repair pathway. Recently, increasing attention has been paid to the role of TDG in tumor development. However, the specific functions of TDG in CRC remain unclear.Methods: The biological functions of TDG and DNA methyltransferase 3 alpha (DNMT3A) in CRC were evaluated using migration and invasion assays, respectively. A tumor metastasis assay was performed in nude mice to determine the in vivo role of TDG. The interaction between TDG and DNMT3A was determined via co-immunoprecipitation (Co-IP). Chromatin immunoprecipitation analysis (ChIP) was used to predict the DNA-binding site of DNMT3A. We also performed methylation-specific PCR (MSP) to detect changes in TIMP2 methylation.Results: TDG inhibited the migration and invasion of human colon cancer cells both in vitro and in vivo. TDG promoted the ubiquitination and degradation of DNMT3A by binding to it. Its interference with siDNMT3A also inhibits the migration and invasion of human colon cancer cells. Furthermore, the ChIP, MSP, and rescue experiments results confirmed that TDG accelerated the degradation of DNMT3A and significantly regulated the transcription and expression of TIMP2, thereby affecting the migration and invasion of human colon cancer cells.Conclusion: Our findings reveal that TDG inhibits the migration and invasion of human colon cancer cells through the DNMT3A-TIMP2 axis, which may be a potential therapeutic strategy for the development and treatment of CRC.

Establishment of Embryonic Zebrafish Xenograft Assays to Investigate TGF-β Family Signaling in Human Breast Cancer Progression.

Transforming growth factor-β (TGF-β) family members have pivotal functions in controlling breast cancer progression, acting not only on cancer cells but also on other cells within the tumor microenvironment. Here we describe embryonic zebrafish xenograft assays to investigate how TGF-β family signaling controls breast cancer cell intravasation, extravasation and regulates tumor angiogenesis. Fluorescently mCherry-labeled breast cancer cells are injected in the perivitelline space or Duct of Cuvier of Tg (fli:EGFP) transgenic Casper zebrafish embryos, in which the zebrafish express enhanced green fluorescent protein in the entire vasculature. The dynamic responses of migratory and invasive human cancer cells, and the induction of new blood vessel formation by the cancer cells in zebrafish host, are visualized using a fluorescent microscope. These assays provide efficient, reliable, low-cost models to investigate the effect of (epi)genetic modulators and pharmacological compounds that perturb the activity of TGF-β family signaling components on breast cancer cell metastasis and angiogenesis.

PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer.

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non‐tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down‐regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/β‐catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion, in vitro and in vivo data demonstrate that PCNP as a tumor suppressor gene may serve as a novel prognostic and potential therapeutic marker in human thyroid cancer.

Clerodane diterpene induces apoptosis/anoikis and suppresses migration and invasion of human bladder cancer cells through the histone deacetylases, integrin–focal adhesion kinase, and matrix metalloproteinase 9 signalling pathways

Clerodane diterpene, a class of bicyclic diterpenoids, is found in hundreds of plant species. 16-hydroxycleroda-3,13-dien-15,16-olide (CD) can be isolated from the plant Polyalthia longifolia and has been applied against oral cancer and glioma by xenograft model. In this study, we aim to explore its antitumour action by examining its histone deacetylase (HDAC) activity and integrin-associated intracellular signalling pathway on T24 human bladder cancer (BC) cells. Our results revealed that CD-inhibited colony formation, HDAC activity, HDAC (1, 2 and 3) mRNA and cell spreading on fibronectin-coated surfaces in a concentration-dependent manner. Furthermore, decreased cFLIP and increased caspase-8 cleavage accompanied CD-induced cell death. At non-toxic concentrations, CD blocked the migration and invasion of T24 cells. CD hindered migration and invasion by the downregulation of fibronectin, integrin α5β1, β-catenin, FAK, vinculin and Rho A, as well as by reduction of phosphorylated glycogen synthase kinase 3β (pGSK3β), pSrc, pstat3 and pNFκB. We observed that the MMP9 gene was closely linked with prognosis of patients with bladder cancer. MMP9 protein levels and activity were largely attenuated by CD in a concentration-dependent manner. In conclusion, CD-induced caspase-8-dependent apoptosis and suppressed migration and invasion by blocking several intracellular signalling pathways, including downregulation of HDAC activity and integrin-FAK and MMP9 pathways.

MiR-142-3p simultaneously targets HMGA1, HMGA2, HMGB1, and HMGB3 and inhibits tumorigenic properties and in-vivo metastatic potential of human cervical cancer cells

AimsHigh-mobility group (HMG) proteins are oncogenic in different cancers, including cervical cancer; silencing their individual expression using sh-RNAs, siRNAs, and miRNAs has had anti-tumorigenic effects, but the consequences of their collective downregulation are not known. Since multiple gene targeting is generally very effective in cancer therapy, the present study highlighted the consequences of silencing the expression of HMGA1, A2, B1, and B3 using sh-RNAs or miR-142-3p (that can potentially target HMGA1, A2, B1, and B3) in cervical cancer cell lines. Main methods3′ UTR luciferase reporter assays were performed to validate HMGA1, A2, B1, and B3 as targets of miR-142-3p in human cervical cancer cells. Annexin V/PI dual staining and flow cytometry analyses were used to detect apoptotic cells. miR-142-3p-mediated regulation of cell death, colony formation, migration, and invasion was investigated in human cervical cancer cells together with in vivo metastasis in zebrafish. Key findingsConcurrent knockdown of HMGA1, A2, B1, and B3 through their corresponding sh-RNAs inhibited cell viability and colony formation but induced apoptosis, and these effects were relatively reduced upon their individual knockdown. miR-142-3p targeted HMGA1, A2, B1, and B3 by binding to their 3′UTRs and induced apoptosis but inhibited proliferation, migration, and invasion of human cervical cancer cells. In addition, miR-142-3p expression decreased phospho-p65 and EMT-related proteins in cervical cancer cells and their in vivo metastatic potential upon implantation in zebrafish. SignificanceThese findings suggest that miR-142-3p acts as a tumor-suppressive miRNA by targeting HMGA1, A2, B1, and B3 and may serve as a potential therapeutic agent in human cervical cancer.

Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression.

Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene. IMPLICATIONS: Our study provides an important clue of how noncoding germline variations contribute to gastric cancer, which gives a novel insight into understanding the genetic mechanism of gastric cancer.

Combination of Auranofin and ICG-001 Suppress the Proliferation and Metastasis of Colon Cancer.

Colon cancer is one of the deadliest tumors in the world, and with high metastasis rate and mortality, effective drugs for its treatment are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, and researchers have found that AF acts as a great antitumor drug in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we aimed to explore the synergistic antitumor effects and the underlying mechanisms of AF and ICG-001 combination therapy on human colon cancer. The results showed that AF and ICG-001 synergistically depressed the growth and invasion of human colon cancer cells by inhibiting the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and its downstream mediator B-cell lymphoma-2-like 1 (Bcl-xL) and inducing caspase-3-dependent apoptosis. Moreover, AF combined with ICG-001 synergistically inhibited the growth of colon cancer in subcutaneous xenograft mice models and restrained metastasis in lung metastasis mice models. In conclusion, our results demonstrated that combination of AF and ICG-001 suppressed the proliferation and metastasis of colon cancer by inhibiting STAT3 phosphorylation. Therefore, this combination therapy may possess potential therapeutic properties for human colon cancer.

TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway

Transmembrane protein (TMEM) is a family of protein that spans cytoplasmic membranes and allows cell–cell and cell–environment communication. Dysregulation of TMEMs has been observed in multiple cancers. However, little is known about TMEM116 in cancer development. In this study, we demonstrate that TMEM116 is highly expressed in non-small-cell lung cancer (NSCLC) tissues and cell lines. Inactivation of TMEM116 reduced cell proliferation, migration and invasiveness of human cancer cells and suppressed A549 induced tumor metastasis in mouse lungs. In addition, TMEM116 deficiency inhibited PDK1-AKT-FOXO3A signaling pathway, resulting in accumulation of TAp63, while activation of PDK1 largely reversed the TMEM116 deficiency induced defects in cancer cell motility, migration and invasive. Together, these results demonstrate that TMEM116 is a critical integrator of oncogenic signaling in cancer metastasis.

Identification and characterization of potent, selective, and efficacious inhibitors of human arylamine N-acetyltransferase 1.

Arylamine N-acetyltransferase 1 (NAT1) plays a pivotal role in the metabolism of carcinogens and is a drug target for cancer prevention and/or treatment. A protein-ligand virtual screening of 2 million chemicals was ranked for predicted binding affinity towards the inhibition of human NAT1. Sixty of the five hundred top-ranked compounds were tested experimentally for inhibition of recombinant human NAT1 and N-acetyltransferase 2 (NAT2). The most promising compound 9,10-dihydro-9,10-dioxo-1,2-anthracenediyl diethyl ester (compound 10) was found to be a potent and selective NAT1 inhibitor with an in vitro IC50 of 0.75µM. Two structural analogs of this compound were selective but less potent for inhibition of NAT1 whereas a third structural analog 1,2-dihydroxyanthraquinone (a compound 10 hydrolysis product also known as Alizarin) showed comparable potency and efficacy for human NAT1 inhibition. Compound 10 inhibited N-acetylation of the arylamine carcinogen 4-aminobiphenyl (ABP) both in vitro and in DNA repair-deficient Chinese hamster ovary (CHO) cells in situ stably expressing human NAT1 and CYP1A1. Compound 10 and Alizarin effectively inhibited NAT1 in cryopreserved human hepatocytes whereas inhibition of NAT2 was not observed. Compound 10 caused concentration-dependent reductions in DNA adduct formation and DNA double-strand breaks following metabolism of aromatic amine carcinogens beta-naphthylamine and/or ABP in CHO cells. Compound 10 inhibited proliferation and invasion in human breast cancer cells and showed selectivity towards tumorigenic versus non-tumorigenic cells. In conclusion, our study identifies potent, selective, and efficacious inhibitors of human NAT1. Alizarin's ability to inhibit NAT1 could reduce breast cancer metastasis particularly to bone.

Shikonin Promotes Apoptosis and Attenuates Migration and Invasion of Human Esophageal Cancer Cells by Inhibiting Tumor Necrosis Factor Receptor-Associated Protein 1 Expression and AKT/mTOR Signaling Pathway.

The aim of this study was to investigate the anticancer effects of shikonin on esophageal cancer (EC) cells and explore the underlying molecular mechanism by identifying dysregulation in shikonin-induced tumor necrosis factor receptor-associated protein 1 (TRAP1) expression. The 3-(4, 5-dimethylthiazol-2-Yl)-2, 5-diphenyltetrazolium bromide assay and EDU assay were performed for cell viability determination. The reactive oxygen species level and mitochondrial membrane potential were evaluated using flow cytometry. The protein expression was detected using Western blot. In addition, cell migration and invasion were estimated. These results demonstrated that shikonin inhibited EC cell growth in a concentration-dependent manner and induced apoptosis through activation of the intracellular apoptotic signaling pathway. Moreover, TRAP1 downregulation promoted shikonin-induced reactive oxygen species release, whereas TRAP1 upregulation blocked it. Meanwhile, shikonin significantly promoted mitochondrial depolarization, accompanied by a large release of cytochrome C. Conversely, shikonin significantly decreased adenosine 5′-triphosphate release, demonstrating a significant intervention in the process of the glucose metabolism. In addition, not only shikonin but also short hairpin RNA (shRNA)-TRAP1 inhibited EC cell migration and invasion. shRNA-TRAP1 enhanced the inhibitory effect of shikonin on matrix metalloproteinase (MMP)2 and MMP9 expression. More interestingly, we demonstrated that shRNA-TRAP1 played a synergistic role in shikonin-mediated regulation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Collectively, shikonin promoted apoptosis and attenuated migration and invasion of EC cells by inhibiting TRAP1 expression and AKT/mTOR signaling, indicating that shikonin may be a new drug for treating EC.

Retraction of: Downregulation of Long Noncoding RNA HOTAIR and EZH2 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Human Breast Cancer Cells (doi: 10.1089/cbr.2017.2432).

Retraction of: Downregulation of Long Noncoding RNA HOTAIR and EZH2 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Human Breast Cancer Cells (doi: 10.1089/cbr.2017.2432).

Retracted] Knockdown of AQP1 inhibits growth and invasion of human ovarian cancer cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Fig.2B and flow cytometric data shown in Fig.3B bore unexpected similarities to data appearing in different form in other articles by different authors. Furthermore, there were additional concerns regarding the possibly anomalous appearance of cell migration data shown in Fig.4B. Owing to the fact that some of the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 16: 5499‑5504, 2017; DOI: 10.3892/mmr.2017.7282].

MK8722, an AMPK activator, inhibiting carcinoma proliferation, invasion and migration in human pancreatic cancer cells

BackgroundMK8722 is a potent and systemic pan-AMPK activator. It is an effective, direct, allosteric activator of AMPK complex in many mammals. This study tried to explore the underlying anti-cancer molecular mechanism of MK8722 in human pancreatic cancer cells (PCCs). MethodsThe anti-proliferation, invasion and migration functions of MK8722 in human pancreatic cancer analyzed by real time cellular analysis, colony formation assay, cell migration assay, transwell assay and flow cytometery analysis. Moreover, the potential targeted signaling pathway was tested via RNA-seq and pathway enrichment analysis. ResultsIn the present study, we investigated the anti-PCCs effects of MK8722 on two different human pancreatic cancer cell lines (PANC-1 and Patu8988). The results showed that MK8722 significantly inhibited human tumor cells proliferation and migration/invasion in a dose-dependent manner. Additionally, the influence of MK8722 was examined by analyzing the expression of potential key genes and pathways, which may provide novel insights to the mechanism of MK8722. ConclusionThe inhibition of pancreatic cancer by MK8722 through a number of pathways that inhibit carcinoma proliferation, invasion and migration. The potential effect of MK8722 might be determined by regulating the expression of AL162151, IER2, REPIN1, KRT80 to inhibit cycle arrest and migration.

DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals.

DEPTOR plays vital roles in the regulation of cell proliferation and survival by directly modulating the activity of mTORC1/2. However, the physiological role of DEPTOR in lung tumorigenesis, as well as its clinical significance, remains elusive. In this study, we revealed that decreased DEPTOR expression correlated with increased tumor size, poor differentiation, and worse survival in patients with lung cancer. DEPTOR depletion promoted cell proliferation, survival, migration, and invasion in human lung cancer cells. Mechanistically, DEPTOR bound to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signal. Thus, DEPTOR depletion not only directly activated mTORC1/2, but also relieved the inhibition of EGFR to subsequently activate mTOR signals, leading to the induction of cell proliferation and survival. Additionally, activated EGFR-mTOR signals upregulated the expression of ZEB1 and SLUG to induce epithelial-mesenchymal transition, resulting in enhanced migration and invasion. Importantly, Deptor deletion accelerated KrasG12D;p53fl/fl-induced lung tumorigenesis and shortened mouse life span via the activation of EGFR-mTOR signals. Collectively, our study demonstrated that DEPTOR acts as a tumor suppressor in lung tumorigenesis, and its reduction may advance the progression of human lung cancer.

MiR-515-5p inhibits the proliferation, migration and invasion of human breast cancer cells by targeting CBX4.

microRNA (miR)-515-5p has been previously suggested to function as a tumor suppressor in various types of human cancer. Therefore, the role of miR-515-5p in breast cancer (BC) was explored in the present study. A series of assays were performed to study the function of miR-515-p in BC cells, including Cell Counting Kit-8, TUNEL, flow cytometric and colony formation to detect cell viability and apoptosis, wound healing and Transwell assays to measure cell motility. In addition, reverse transcription quantitative PCR and western blot analysis were used to assess miR-515-5p, CBX4, Cox-2, MMP2, MMP9, CDK2, p21 and Cyclin D1 respectively. Bioinformatics and dual-luciferase reporter assays were used to analyze the target genes of miR-515-5p, which confirmed the direct binding between miR-515-5p and polycomb chromobox 4 (CBX4). It was found that the expression of miR-515-5p is lower in BC cells compared with that in normal breast cells (MCF10A). Overexpression of miR-515-5p using the miR-515 mimic was found to reduce cell viability, facilitate cell apoptosis, inhibit cell proliferation and arrest cell cycle progressio at G1 phase. In addition, miR-515-5p overexpression could inhibit cell migration and invasion, whilst decreasing the expression levels of prostaglandin-endoperoxide synthase 2, MMP2 and MMP9 proteins. In addition, miR-515-5p overexpression could reduce the expression levels of CBX4 in MCF7 and ZR-75-30 cells. By contrast, overexpression of CBX4 reversed the effects of the miR-515-5p mimic transfection on cell proliferation, migration and invasion in MCF7 and ZR-75-30 cells. In combination, these results suggest that miR-515-5p inhibits BC cell proliferation, migration and invasion by directly targeting CBX4.

Galangin Enhances Anticancer Efficacy of 5-Fluorouracil in Esophageal Cancer Cells and Xenografts Through NLR Family Pyrin Domain Containing 3 (NLRP3) Downregulation.

BackgroundGalangin is believed to exert antioxidant effects by inhibition of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, which has been linked to chemotherapy sensitivity in cancers. In this study, we explored the synergistic effect of galangin in combination with the chemotherapy agent 5-fluorouracil (5-FU) in esophageal cancer cells and xenografts.Material/MethodsThe esophageal squamous epithelium cell line Het-1A and 2 human esophageal cancer cell lines (Eca109, OE19) were used to investigate the effect of galangin with or without 5-FU in vitro through proliferation and invasion analyses, while apoptosis was analyzed in cancer cells. Furthermore, a subcutaneous xenograft tumor model in mice was used to study cancer development in vivo.ResultsCompared with 5-FU monotherapy, combined galangin and 5-FU treatment reduced human esophageal cancer cell growth activities and invasion abilities. The results suggested that galangin had a chemotherapy-sensitized synergistic antitumor effect induced by 5-FU. The susceptibility of cancer cells to apoptosis, which is linked with chemotherapy sensitivity, was induced by 5-FU and further enhanced by galangin. NLRP3 was identified as being significantly activated by 5-FU, but galangin treatment reversed the effect and inhibited NLRP3 expression, which was accompanied by downregulated interleukin-1β levels. Further investigation showed that the induced apoptotic cascade can be mostly reversed by incubation with an NLRP3 activator, irrespective of AKT signaling. Using xenograft mouse models, we found that galangin exposure further restrained cancer development after 5-FU treatment and increased sensitivity to chemotherapy by suppressing the NLRP3 inflammasome pathway.ConclusionsOur results indicated that galangin played a synergistic anticancer role through NLRP3 inflammasome inhibition when paired with FU-5.

Retraction: Oncoproteins of High-Risk HPV and EBV Cooperate to Enhance Cell Motility and Invasion of Human Breast Cancer Cells via Erk1/Erk2 and β-Catenin Signaling Pathways.

[This retracts the article DOI: 10.3389/fonc.2021.630408.].