Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway.
Notch3 is one of the four Notch receptors identified in mammal, but its role in human pancreatic cancer remains poorly characterized. In this study, we sought to determine the effect of suppressing Notch3 expression on the chemosensitivity to gemcitabine in human pancreatic cancer cell lines BxPC-3 and PANC-1. RNA interference was used to suppress Notch3 expression. Gemcitabine-induced cytotoxicity was determined by MTT. Cell apoptosis was measured by flow cytometry. Caspase 3 activity was assayed using a Caspase Fluorescent Assay Kit. The effect of Notch3-specific siRNA on PI3K/Akt activity was also quantified. Notch3-specific siRNA suppressed Notch3 expression, and furthermore increased gemcitabine-induced, caspase-mediated apoptosis. The suppression of Notch3 expression decreased the average IC(50) in BxPC-3 and PANC-1 cells treated with gemcitabine. PI3K/Akt activity was decreased by the suppression of Notch3 expression. Taken together, these data demonstrated that Notch3 is a potential therapeutic target for pancreatic cancer, and PI3K/Akt is a key signaling component by which activation of the Notch3 signal transduction pathway protects pancreatic cancer cells from chemotherapy-induced cell death.
Yao
Jun
J
School of Medicine, Taizhou University, Jiaojiang District, 318000, Taizhou, Zhejiang, China. yaojuntzu@yeah.net
Qian
Cuijuan
C
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C499374:NOTCH3 protein, human; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D003841:Deoxycytidine; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine