Biomaterial Database

Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. 2009

Ruben Plentz, and Ji-Sun Park, and Andrew D Rhim, and Daniel Abravanel, and Aram F Hezel, and Sreenath V Sharma, and Sushma Gurumurthy, and Vikram Deshpande, and Candia Kenific, and Jeffrey Settleman, and Pradip K Majumder, and Ben Z Stanger, and Nabeel Bardeesy

Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.

OBJECTIVE The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression. METHODS We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice). RESULTS Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumor-derived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P < .005, chi2 test; compared with mice exposed to vehicle). CONCLUSIONS These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.

UI	MeSH Term	Description	Entries
D008822	Mice, Transgenic	Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.	Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D010190	Pancreatic Neoplasms	Tumors or cancer of the PANCREAS. Depending on the types of ISLET CELLS present in the tumors, various hormones can be secreted: GLUCAGON from PANCREATIC ALPHA CELLS; INSULIN from PANCREATIC BETA CELLS; and SOMATOSTATIN from the SOMATOSTATIN-SECRETING CELLS. Most are malignant except the insulin-producing tumors (INSULINOMA).	Cancer of Pancreas,Pancreatic Cancer,Cancer of the Pancreas,Neoplasms, Pancreatic,Pancreas Cancer,Pancreas Neoplasms,Pancreatic Acinar Carcinoma,Pancreatic Carcinoma,Acinar Carcinoma, Pancreatic,Acinar Carcinomas, Pancreatic,Cancer, Pancreas,Cancer, Pancreatic,Cancers, Pancreas,Cancers, Pancreatic,Carcinoma, Pancreatic,Carcinoma, Pancreatic Acinar,Carcinomas, Pancreatic,Carcinomas, Pancreatic Acinar,Neoplasm, Pancreas,Neoplasm, Pancreatic,Neoplasms, Pancreas,Pancreas Cancers,Pancreas Neoplasm,Pancreatic Acinar Carcinomas,Pancreatic Cancers,Pancreatic Carcinomas,Pancreatic Neoplasm
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D003499	Cyclic S-Oxides		Heterocyclic S-Oxides,Cyclic S Oxides,Heterocyclic S Oxides,Oxides, Cyclic S,S Oxides, Cyclic,S-Oxides, Cyclic,S-Oxides, Heterocyclic
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013830	Thiadiazoles	Heterocyclic compounds composed of a five-membered heterocyclic ring which contains one sulfur and two nitrogen atoms.	Thiadiazole
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D045744	Cell Line, Tumor	A cell line derived from cultured tumor cells.	Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus