Targeting the <scp>N</scp>otch signaling pathway in cancer therapeutics

Guo, Hangyuan; Lü, Yi; Wang, Jianhua; Liu, Xia; Keller, Evan T.; Liu, Qian; Zhou, Qinghua; Zhang, Jian

doi:10.1111/1759-7714.12143

Cited by 38 publications

(27 citation statements)

References 184 publications

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“…Notch expression is enhanced in the tubule cells of fibrotic kidneys from diabetic mice and humans and Notch interacting proteins have been identified that may be pertinent in normal and pathological functioning (21). The present study additionally demonstrated that HG activated the Notch pathway in a time-dependent manner in HKC cells and the maximum expression of Notch1 and NICD1 was observed at 24 h. HG increases Notch1 expression and releases NICD1, which travels into the nucleus and activates the downstream genes in HKC cells (22,23). DAPT, a Notch pathway inhibitor, suppresses activation of the Notch pathway by HG, which may inhibit γ-secretase-mediated proteolytic cleavage of Notch, reducing the release of the NICD from the plasma membrane into the nucleus (10).…”

Section: Discussionsupporting

confidence: 69%

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Yao

Gao

Shi

et al. 2017

Molecular Medicine Reports

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It has previously been demonstrated that nicotinamide adenine dinucleotide phosphate‑oxidase (NADPH) oxidase 4 (Nox4), is important in the pathogenesis of diabetic nephropathy (DN), however the exact mechanisms remain to be elucidated. The present study aimed to examine the effect of Nox4 on the alteration of the Notch pathway and cell apoptosis in the renal tubular epithelial cell line, HKC, under conditions of high glucose (HG; 30 mmol/l glucose). Nox4 and the Notch pathway were inhibited by N‑acetylcysteine (NAC), diphenylene iodonium (DPI) or γ‑secretase inhibitor (DAPT). The protein levels of Nox4, Notch1, Notch intracellular domain 1 (NICD1), phosphorylated (p) Ras‑related C3 botulinum toxin substrate 1 (Rac1), Rac1, B‑cell lymphoma 2 apoptosis regulator (Bcl‑2), Bcl‑2 associated protein X apoptosis regulator (Bax) and cleaved caspase‑3 were determined by western blotting. The Nox4 and Notch1 mRNA levels were detected by reverse transcription‑quantitative polymerase chain reaction. Intracellular reactive oxygen species (ROS) levels were detected via chloromethyl‑2',7'‑dichlorodihydrofluorescein diacetate. Apoptotic cells were determined using an Annexin V/propidium iodide apoptosis detection kit. HG upregulated Nox4, Notch1, NICD1, p‑Rac1, Bax and cleaved caspase‑3 expression levels and downregulated Bcl‑2 expression in cultured HKC cells, compared with cells cultured in normal glucose levels. Inhibition of the Notch pathway via DAPT increased Bcl‑2 expression, decreased Bax and cleaved caspase‑3 levels and prevented HKC cell apoptosis. Inhibition of Nox4 by NAC and DPI inhibited the Notch signaling pathway and ROS generation, which prevented HKC cell apoptosis. These findings indicated that Nox4 potentially mediates HG‑induced HKC cell apoptosis via the Notch pathway, and may be involved in renal tubular epithelial cell injury in DN.

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Section: Discussionsupporting

confidence: 69%

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Yao

Gao

Shi

et al. 2017

Molecular Medicine Reports

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“…10,11 Although the role of different Notch transmembrane receptors in NSCLC development is not completely understood, Notch-1 is considered to play a vital role in cancer development [12][13][14][15] compared with other Notch transmembrane receptors. For instance, Notch-1 shows a growth-promoting function on NSCLC, whereas in SCLC, it plays a tumor-suppressive role.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, Notch-1 shows a growth-promoting function on NSCLC, whereas in SCLC, it plays a tumor-suppressive role. 12 Baumgart et al 13 reported that Notch-1 expression from excessive ADAM17 activities leads to subsequent regulation of the epidermal growth factor receptor expression and tumorigenicity of NSCLC cells. Overexpression of Notch-1 has also been reported to inhibit apoptosis in lung adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

Rajasinghe¹,

Gupta²

2017

NDS

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Abstract:Lung cancer is one of the leading causes of cancer deaths. Non-small cell lung cancer (NSCLC), with a 5-year survival rate of 5% at stage IIIB, accounts for 80%-85% of all lung cancers. Aberrant Notch-1 expressions have been reported in lung cancer patients and could potentially be a beneficial molecular/therapeutic target against NSCLC. Tocotrienols, isomers of vitamin E, have been shown to exhibit antitumor activity via inhibition of different signaling pathways in tumor cells. Previously, we reported that delta-tocotrienol downregulates Notch-1 via NF-κB. However, the pure isomers are presently not available in quantities required for animal or clinical studies. Therefore, the objective of this study was to investigate the interactions and effects of commercially available tocotrienols (a mixture of isomers) on the Notch-1 pathway in NSCLC, adenocarcinoma (A549) and squamous cell lung cancer (H520) cell lines. A dose-dependent decrease in all growth, cell migration, and tumor invasiveness was observed in both cancer cell lines with the addition of tocotrienols. A significant induction of apoptosis was also observed using Annexin V stain in flow cytometry analysis. Since tocotrienols significantly affected proliferation, apoptosis, migration, and invasiveness, reverse transcription polymerase chain reaction and Western blot analysis were used to explore the molecular mechanisms responsible for the regulations by testing the expression of Notch-1 and its downstream genes. A dose-dependent decrease in expression of proteins was observed in Notch-1, Hes-1, Survivin, and Bcl-XL. In addition, we found a mechanism linking the NF-κB pathway and Notch-1 down-regulation from NF-κB DNA-binding activities. Thus, our data suggest that commercially available tocotrienols inhibits cell growth, migration, and tumor cell invasiveness via downregulation of Notch 1 and NF-κB while inducing apoptosis. Hence, these commercially available tocotrienol-rich mixture could potentially be an effective supplementation for lung cancer prevention.

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“…The r-secretase inhibitor of Notch pathway GSIs could prevent cleavage of r-secretase and keeping it to cell membrane thus inhibit Notch signal pathway. Inhibition of Notch signal pathway could inhibit cell proliferation and promote cell differentiation [18][19][20][21]. Besides, inhibition of Hedgehog signal pathway could also inhibit tumor effectively, having promised effect in clinic [22].…”

Section: Inhibition Of Self-renew Signal Pathwaymentioning

confidence: 99%

“…They plays very important role in CSCs maintenance as well. Notch pathway in endothelial cells significant promote the stemness of brain CSCs [18,20]. Developing the drugs targeting the micro-environment of CSCs will eliminate CSCs, the root of cancer.…”

Section: Cancer Micro-environmentmentioning

confidence: 99%

Dig the root of cancer: targeting cancer stem cells therapy

Xu¹,

Liu²,

Xiao³

et al. 2017

JMD

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Cancer stem cells are a subpopulation of cancer cells which have stem cell characteristics and play vital role in tumor formation, metastasis, relapse and resistance to chemo-drugs. Exploring drugs or designing novel approaches to target cancer stem cells will contribute greatly to cancer therapy. The first step of exploring effective drugs to cancer stem cells is to acquire cancer stem cells and characterize their properties. Developing the targeting drugs could be based on the characteristics of cancer stem cells, like signal pathways contributing to self-renew, ability to pump small molecules out and quiescence. This review will summarizing the current approaches of designing drugs to target cancer stem cells.

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Targeting the Notch signaling pathway in cancer therapeutics

Cited by 38 publications

References 184 publications

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

Dig the root of cancer: targeting cancer stem cells therapy

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Targeting the Notch signaling pathway in cancer therapeutics

Cited by 38 publications

References 184 publications

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-&kappa;B pathways in NSCLC cells

Dig the root of cancer: targeting cancer stem cells therapy

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Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells