Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

Wu, Chuan; Xu, Anjian; Zhang, Cathy C.; Olson, Peter; Cc, Lin; Lee, Terence; Cheung, Tan To; Lo, Chung Mau; Wang, Xiao Qi

doi:10.1158/1535-7163.mct-17-0001

Cited by 62 publications

(61 citation statements)

References 38 publications

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“…Previous studies have shown that the γ-secretase complex, comprised of PS-1, APH-1, PEN-2 and NCSTN, is recognized as a therapeutic option for treating HCC [10,[20][21][22]. However, inhibitors of the γ-secretase complex are well known to have serious adverse effects, as they are not cell selective or system specific [23].…”

Section: Discussionmentioning

confidence: 99%

Effect of nicastrin on hepatocellular carcinoma proliferation and apoptosis through PI3K/AKT signalling pathway modulation

Wang

et al. 2020

Cancer Cell Int

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Background: Increasing evidence has proven that the γ-secretase complex plays significant roles in the carcinogenesis of malignancies. However, the independent effect of nicastrin (NCSTN), the largest constituent of the γ-secretase complex, on the progression of hepatocellular carcinoma (HCC) remains to be discovered. Methods:In our study, we used open online databases, including the Oncomine database, GEPIA and KMPlotter, to analyse the expression of 4 genes and their correlation with prognosis in HCC. NCSTN expression in 60 HCC patients from our centre was determined by immunohistochemical staining and qRT-PCR. The clinical and prognostic significance of NCSTN expression were analysed statistically. Stable Sk-hep1 cell lines with NCSTN overexpression were established using lentivirus-based vectors, and RNAi technology was used to transiently downregulate NCSTN expression in HepG2 cell lines. Cell growth and apoptosis were assessed by using EdU, clone formation, flow cytometry and Western blotting assays.Results: Bioinformatics analysis showed that NCSTN mRNA expression was generally higher in HCC tissues than in normal tissues according to a meta-analysis of 9 HCC datasets, excluding PS-1, PEN-2 and APH-1. Moreover, NCSTN was associated with a poor prognosis in HCC patients from The Cancer Genome Atlas (TCGA). Although the relationship between NCSTN levels and the clinicopathological features of HCC patients was not significant, a survival analysis of HCC patients from TCGA indicated that overall and disease-free survival were significantly associated with NCSTN expression. NCSTN expression in HCC cell lines regulated cell growth and apoptosis in vitro. NCSTN downregulation in HepG2 cells inhibited tumour growth ability in vivo. In addition, NCSTN downregulation in HepG2 cell lines decreased p-PI3K and p-Akt expression, and IGF1, a PI3K/Akt activator, neutralized the effects on PI3K and Akt phosphorylation. Moreover, NCSTN overexpression in Sk-hep1 cells activated the PI3K/Akt signalling pathway, and MK-2206, a PI3K/Akt inhibitor, reversed this activation according to Western blotting analysis. Conclusions:We suggest that NCSTN serves as an oncogene in HCC by promoting growth and inhibiting apoptosis via the PI3K/Akt pathway, providing a potential novel therapeutic target for HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Effect of nicastrin on hepatocellular carcinoma proliferation and apoptosis through PI3K/AKT signalling pathway modulation

Wang

et al. 2020

Cancer Cell Int

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“…PF-3804014 [a novel gamma-secretase inhibitor (Lanz et al, 2010) that has been used in recent studies to inhibit Notch signaling (e.g., Samon et al, 2012;Wu et al, 2017); Tocris Bioscience, United Kingdom] treatment after a complete SCI (see previous paragraph) was done as previously described for taurine treatments (Sobrido-Cameán et al, 2019). In these experiments, PF-3804014 was dissolved in lamprey Ringer solution (137 mM NaCl, 2.9 mM KCl, 2.1 mM CaCl2, 2 mM HEPES; pH 7.4) at a concentration of 5 mM, soaked in a small piece of Gelfoam (Pfizer; New York, NY) and placed on top of the site of injury at the time of spinal cord transection.…”

Section: Animals Sci and Drug Treatmentsmentioning

confidence: 99%

Inhibition of Gamma-Secretase Promotes Axon Regeneration After a Complete Spinal Cord Injury

Sobrido‐Cameán

Robledo

Romaus-Sanjurjo

et al. 2020

Front. Cell Dev. Biol.

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In a recent study, we showed that GABA and baclofen (a GABAB receptor agonist) inhibit caspase activation and promote axon regeneration in descending neurons of the sea lamprey brainstem after a complete spinal cord injury (Romaus-Sanjurjo et al., 2018a). Now, we repeated these treatments and performed 2 independent Illumina RNA-Sequencing studies in the brainstems of control and GABA or baclofen treated animals. GABA treated larval sea lampreys with their controls were analyzed 29 days after a complete spinal cord injury and baclofen treated larvae with their controls 9 days after the injury. One of the most significantly downregulated genes after both treatments was a HES gene (HESB). HES proteins are transcription factors that are key mediators of the Notch signaling pathway and gamma-secretase activity is crucial for the activation of this pathway. So, based on the RNA-Seq results we subsequently treated spinal cord injured larval sea lampreys with a novel gamma-secretase inhibitor (PF-3804014). This treatment also reduced the expression of HESB in the brainstem and significantly enhanced the regeneration of individually identifiable descending neurons after a complete spinal cord injury. Our results show that gamma-secretase could be a novel target to promote axon regeneration after nervous system injuries.

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“…Osteosarcoma is the most common primary malignant bone tumor, and is most commonly seen in the distal femur and metaphysis of the upper tibia [1]. The degree of malignancy in osteosarcoma is very high, and approximately 80–90% of patients present with metastasis [1].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The degree of malignancy in osteosarcoma is very high, and approximately 80–90% of patients present with metastasis [1]. Most osteosarcomas metastasize to the lungs, with a few spreading to the brain, prostate, kidney, and other organs [1]. Prior to the 1970s, osteosarcoma was mainly treated with amputation, but the 5-year survival rate was only 15–20% [2, 3].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-330-3p Expression Indicates Good Prognosis and Suppresses Cell Proliferation by Targeting Bmi-1 in Osteosarcoma

Zheng

Feng

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Growing evidence has shown that miR-330-3p is closely related to the biological behavior of cancer, including proliferation, metastasis, and prognosis. However, there have been no reports on miR-330-3p expression and function in osteosarcoma. Methods: Expression of miR-330-3p in osteosarcoma tissues and cell lines was examined by quantitative PCR. Effects of miR-330-3p on osteosarcoma cell proliferation were investigated in vitro with the Cell Counting Kit-8 colorimetric assay. Targets of miR-330-3p were identified by dual-luciferase reporter assay. Results: The results showed that expression of miR-330 decreased in osteosarcoma tissues and cell lines. Prognosis of patients with high miR-330-3p expression was much better than that of those with low expression (P=0.001), and multivariate analysis suggested that miR-330-3p is an independent prognostic factor for osteosarcoma. In addition, miR-330-3p overexpression significantly inhibited the growth of MG-63 and U2OS osteosarcoma cells. Dual-luciferase reporter assay demonstrated that Bmi-1 was a direct target gene of miR-330-3p, and in a recovery experiment, miR-330-3p suppressed osteosarcoma cell proliferation by directly targeting Bmi-1. Conclusion: Our results suggest that miR-330-3p acts as a tumor suppressor by regulating Bmi-1 expression in osteosarcoma. Thus, miR-330-3p may represent a novel therapeutic target for the treatment of osteosarcoma.

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Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

Cited by 62 publications

References 38 publications

Effect of nicastrin on hepatocellular carcinoma proliferation and apoptosis through PI3K/AKT signalling pathway modulation

Effect of nicastrin on hepatocellular carcinoma proliferation and apoptosis through PI3K/AKT signalling pathway modulation

Inhibition of Gamma-Secretase Promotes Axon Regeneration After a Complete Spinal Cord Injury

MicroRNA-330-3p Expression Indicates Good Prognosis and Suppresses Cell Proliferation by Targeting Bmi-1 in Osteosarcoma

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