Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3

Sk, Ahn; Yang, Ji Hye; Kim, Nam Hee; Lee, Kyungro; Hoon, Yong; Yun, Jung Won; Kang, Hee Eun; Lee, Yoonmi; Choi, Jiwon; Kim, Hyun Sil; Yook, Jong In

doi:10.18632/oncotarget.16255

Cited by 23 publications

(20 citation statements)

References 30 publications

(42 reference statements)

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“…Many studies have reported on the niclosamide enhances cytotoxicity on various cancers, including oral cancer, lung cancer, colon, thyroid, cervix, ovarian, kidney, and prostate cancers, via STAT3, EGFR/PI3K/Akt, RANKL Wnt, mTOR, HIF‐1α/VEGF, Ras, c‐myc, and Notch signal pathways and mitochondria dysfunction 11, 12, 13, 14, 26, 27, 28, 29, 30, 31, 32, 33. Cancer cell upregulates other important downstream genes such as STAT3, which contributes to cell proliferation, cell survival, and angiogenesis in many cancers.…”

Section: Discussionmentioning

confidence: 99%

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

Chen

Huang

et al. 2018

Cancer Medicine

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The incidence and mortality rate of urological cancers is increasing yearly. Niclosamide has been repurposed as an anti‐cancer drug in recent years. Synthesized derivative of niclosamide was testified for its anti‐cancer activity in urological cancers. MTT assay was used to measure the cytotoxicity effect of niclosamide and its derivatives in urological cancer cell lines. Migratory ability was monitored by scratch migration assay. Apoptosis and cell cycle changes were analyzed by annexin V and PI staining. The apoptosis‐related signal proteins were evaluated by western blotting. T24 had the best drug sensitivity with the lowest IC 50 in niclosamide and B17 treatment than DU145 and Caki‐1 cells. After niclosamide and B17 treatment, the mitotic cells were decreased, but apoptotic bodies and morphology changes were not prominent in T24, Caki‐1, and DU145 cells. The migratory ability was inhibited in niclosamide treatment than control group on Caki‐1 cells and niclosamide and B17 treatment than control group on DU145 cells. Early apoptosis cells were increased after niclosamide and B17 treatment than control group without cell cycle changes in T24, Caki‐1, and DU145 cells. Programmed cell death was activated majorly through PAPR and bcl‐2 in T24 and caspase‐3 in Caki‐1 cells, respectively. Niclosamide and B17 derivative had good ability in inhibition proliferation and migratory ability in T24, Caki‐1, and DU145 cells without prominent morphology and apoptotic body changes. UCC cells are more sensitive to niclosamide and B17 treatment. Early apoptosis was induced after niclosamide and B17 treatment through different mechanisms in T24, Caki‐1, and DU145 cells.

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Section: Discussionmentioning

confidence: 99%

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

Chen

Huang

et al. 2018

Cancer Medicine

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“…Other specific GSK3β inhibitors include the small chemicals TDZD8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) and TWS119 (4,6-disubstituted pyrrolopyrimidine) and the peptide L803-mts [N-myristol-GKEAPPAPPQS(p)P] (65). In addition, niclosamide, a U.S. Food and Drug Administration approved salicyclamide derivative anthelmintic drug used for the treatment of tapeworm infections, binds to GSK3β and inhibits WNT pathway functions (66). DIF [1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one], a putative morphogen produced by Dictyostelium discoideum, suppresses the WNT/β-catenin signaling pathway via the activation of GSK3β and subsequently reduces the expression levels of c-Myc and cyclin D1 (67).…”

Section: Gsk3β Modulators [Prodigiosin Tdzd8 T Ws119 L803-mts Tidmentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

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“…Other studies reported the crosstalk between Wnt/β-catenin and Ras-Erk pathways in the colorectal tumorigenesis [54,55]. Wnt signaling is involved in the stability of Ras through regulation of glycogen synthase kinas 3β-mediated Ras phosphorylation [56]. In hepatocellular carcinoma, Wnt signaling modulates lipid homeostasis in a Ras-dependent manner [57].…”

Section: Discussionmentioning

confidence: 98%

NUDT7 Loss Promotes KrasG12D CRC Development

Song

Park

et al. 2020

Cancers

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Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.

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Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3

Cited by 23 publications

References 30 publications

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

NUDT7 Loss Promotes KrasG12D CRC Development

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