Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

Radke, David I; Ling, Qi; Häsler, Robert; Alp, Gökhan; Ungefroren, Hendrik; Trauzold, Anna

doi:10.3390/cancers10110399

Cited by 14 publications

(14 citation statements)

References 62 publications

(74 reference statements)

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“…TRAIL can trigger the apoptosis cascades by activating death receptors in the cell membrane and inducing the activation of initiator caspase in the extrinsic apoptosis pathway [5]. Although TRAIL is a promising antitumor agent, various cancer cell lines, including HCC cell lines, develop resistance to TRAIL-induced apoptosis [6,7]. Thus, researchers are trying to discovery novel drugs to sensitize the HCC cell to TRAIL-induced apoptosis, while sparing normal cells and tissues.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by TRAIL. A recent study found that shikonin b (alkannin, 5,8-dihydroxy-2-[(1S)-1-hydroxy-4-methylpent-3-en-1-yl]naphthalene-1,4-dione) might induce apoptosis in TRAIL-resistant cholangiocarcinoma cells through reactive oxygen species (ROS)-mediated caspases activation. However, the strong cytotoxic activity has limited its potential as an anticancer drug. Thus, the current study intends to discover novel shikonin derivatives which can sensitize the liver cancer cell to TRAIL-induced apoptosis while exhibiting little toxicity toward the normal hepatic cell. The trypan blue exclusion assay, western blot assay, 4′,6-diamidino-2-phenylindole (DAPI) staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay as well as the ‘comet’ assay, were used to study the underlying mechanisms of cell death and to search for any mechanisms of an enhancement of TRAIL-mediated apoptosis in the presence of ASH. Herein, we demonstrated that non-cytotoxic doses of acetylshikonin (ASH), one of the shikonin derivatives, in combination with TRAIL, could promote apoptosis in HepG2 cells. Further studies showed that application of ASH in a non-cytotoxic dose (2.5 μM) could increase intracellular ROS production and induce DNA damage, which might trigger a cell intrinsic apoptosis pathway in the TRAIL-resistant HepG2 cell. Combination treatment with a non-cytotoxic dose of ASH and TRAIL activated caspase and increased the cleavage of PARP-1 in the HepG2 cell. However, when intracellular ROS production was suppressed by N-acetyl-l-cysteine (NAC), the synergistic effects of ASH and TRAIL on hepatocellular carcinoma (HCC) cell apoptosis was abolished. Furthermore, NAC could alleviate p53 and the p53 upregulated modulator of apoptosis (PUMA) expression induced by TRAIL and ASH. Small (or short) interfering RNA (siRNA) targeting PUMA or p53 significantly reversed ASH-mediated sensitization to TRAIL-induced apoptosis. In addition, Bax gene deficiency also abolished ASH-induced TRAIL sensitization. An orthotopical HCC implantation mice model further confirmed that co-treated ASH overcomes TRAIL resistance in HCC cells without exhibiting potent toxicity in vivo. In conclusion, the above data suggested that ROS could induce DNA damage and activating p53/PUMA/Bax signaling, and thus, this resulted in the permeabilization of mitochondrial outer membrane and activating caspases as well as sensitizing the HCC cell to apoptosis induced by TRAIL and ASH treatment.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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“…Among numerous candidates with strict stringency, miR-370-3p exhibited the highest increase in circAGFG1-silenced CC cells, compared with control cells (Additional file 1: Figure S1A). Previous studies have reported that miR-370-3p can function as a tumor suppresser and be absorbed by circRNAs in different kinds of cancers [11, 18, 19]. Here we carried out FISH assay to elucidate the subcellular location of circAGFG1 and miR-370-3p.…”

Section: Resultsmentioning

confidence: 99%

“…In our research, circAGFG1, miR-370-3p and RAF1 constituted a ceRNA network to regulate cervical cancer cellular processes. MiR-370-3p has been indicated to participate in pancreatic cancer, glioblastoma and bladder cancer and so on [11–13]. Serine/threonine kinase (RAF1), also names Raf-1 proto-oncogene, is a well-known oncogene in multiple carcinomas, such as lung cancer, glioma and gastric cancer [14–16].…”

Section: Introductionmentioning

confidence: 99%

CircAGFG1 promotes cervical cancer progression via miR-370-3p/RAF1 signaling

Zhou

2019

BMC Cancer

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BackgroundIn past decades, circular RNAs (circRNAs) have achieved increasing attention because of its regulatory role in different kinds of cancers. However, how circAGFG1 regulates cervical cancer (CC) is still largely undiscovered. This study aims to evaluate the role of a novel circRNAs and related molecular mechanism in CC cells.MethodsHigh or low level of circAGFG1 was detected in CC cells or normal cell line with qRT-PCR. The proliferative and migratory abilities of CC cells were assessed with loss-of function assays. The downstream miRNA and mRNA of circAGFG1 were searched out and proved by using bioinformatics analysis and mechanism experiments. Recue assays were designed to confirm the role of circAGFG1/miR-370-3p/RAF1 axis in CC cell activities.ResultsThe levels of circAGFG1 was abundant in CC cells in comparison with normal cervical cell End1/E6E7. The inhibitory effect of decreased circAGFG1 level on the proliferative and migratory abilities of CC cells was assessed. CircAGFG1 and miR-370-3p were localized in the cytoplasm and they can interact with each other. Moreover, miR-370-3p was downregulated in CC cells. We also determined the negative effect of miR-370-3p on RAF1. CircAGFG1 could promote RAF1 expression by absorbing miR-370-3p, thereby activating RAF/MEK/ERK pathway. circAGFG1 promoted proliferation and migration of CC cells via enhancing the activity of RAF/MEK/ERK pathway by sponging miR-370-3p and further regulating RAF1.ConclusionThe results of this study provided new evidence that circAGFG1 acted as a vital regulator in cervical cancer proliferation and migration, giving great promise to apply it as a potential biomarker for diagnosis and therapy in CC treatment.

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“…17,18 TRAIL is a ligand that induces apoptosis or necroptosis by binding to transmembrane death receptors that promote the formation of death-inducing signaling and activation of the caspase pathway, leading to apoptotic tumor cell death. [19][20][21] However, malignant tumor cells may produce resistance to TRAIL therapy. 22 Thus, effective therapeutic methods are required to combine with TRAIL to improve the targeted therapy effect or reverse the resistance to TRAIL.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma

Zhang

Huang

et al. 2020

Human Gene Therapy

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Oncolytic adenoviruses (OAds) are promising agents for cancer therapy, representing a novel therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC). However, there are challenges associated with the successful use of an OAd alone, involving the security of the viral vector and screening of an effective antitumor gene. In the present study, a novel OAd CD55-ST13-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was constructed in which the dual therapeutic genes ST13 and TRAIL were inserted, featuring the carcinoembryonic antigen (CEA) as a promoter to control E1A and deletion of the 55 kDa E1B gene. ST13, known as a colorectal cancer suppressor gene, exhibited lower expression in PDAC than in tumor-adjacent tissues and was associated with poor prognosis in PDAC patients. In vitro studies demonstrated that CD55-ST13-TRAIL was effective in promoting the expression of ST13 and TRAIL in CEApositive pancreatic cancer cells. Moreover, CD55-ST13-TRAIL exhibited a synergistic effect toward tumor cell death compared with CD55-ST13 alone or CD55-TRAIL alone, and inhibited tumor cell proliferation and induced cell apoptosis dependent on caspase pathways in PDAC cells. Furthermore, xenograft experiments in a mouse model indicated that CD55-ST13-TRAIL significantly inhibited tumor growth and improved the survival of animals with xenografts. The findings demonstrate that oncolytic virotherapy under the control of the promoter CEA enables safe and efficient treatment of PDAC, and suggest that it represents a promising candidate for the treatment of metastatic diseases.

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Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

Cited by 14 publications

References 62 publications

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

CircAGFG1 promotes cervical cancer progression via miR-370-3p/RAF1 signaling

Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma

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