γ-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers

Konishi, Jun; Kawaguchi, Keiko; Vo, Huan; Haruki, Nobuhiro; González, Adriana; Carbone, David P.; Dang, Thao P.

doi:10.1158/0008-5472.can-07-1022

Cited by 238 publications

(217 citation statements)

References 30 publications

Supporting

Mentioning

201

Contrasting

Order By: Relevance

“…Previous studies also documented that Notch1 was frequently expressed in lung cancer and correlated with the malignancy of NSCLC (Collins et al, 2004). In contrast, recent studies have demonstrated reduced or even undetectable Notch1 expression in NSCLC, implying its tumor-suppressive role in NSCLC Konishi et al, 2007). To explore the precise mechanism involved in the interaction between endothelial Dll4 and Notch receptors of NSCLC, we examined the mRNA levels of Notch in A549 cells cocultured with ECs.…”

Section: Resultsmentioning

confidence: 95%

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Ding

et al. 2011

Oncogene

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 95%

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Ding

et al. 2011

Oncogene

View full text Add to dashboard Cite

“…DAPT reduces ductal carcinoma in situ mammosphere formation (Farnie et al, 2007) and pancreatic cancer cell growth (Kimura et al, 2007). Another g-secretase inhibitor, MRK-003, reduces tumour cell proliferation, inhibits serum independence, and induces apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models (Konishi et al, 2007). Thus, the g-secretase complex is now becoming an accepted target in cancer therapy, in particular, with regard to Notch signalling (Shih and Wang, 2007).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

et al. 2009

View full text Add to dashboard Cite

g-Secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different g-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 mM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in g-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the g-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the g-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.

show abstract

“…The hypothesis that γ-secretase inhibitors would have caused GBM TIC cell death was mainly based on recently published literature, which reported that γ-secretase inhibitors kill Kaposi's tumor cell lines (38), enhance chemotherapy-induced apoptosis in colon cancer cells (39) and in myeloma cells (40), and reduce the proliferation of lung cancer cells (41).…”

Section: Discussionmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

show abstract

γ-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers

Abstract: Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms.

Cited by 238 publications

References 30 publications

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Contact Info

Product

Resources

About