title: Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy.
abstract: Pancreatic cancer is one of the most lethal tumor types worldwide and an effective therapy is still elusive. Targeted therapy focused against a specific alteration is by definition unable to attack broad pathway signaling modification. Tumor heterogeneity will render targeted therapies ineffective based on the regrowth of cancer cell sub-clones. Therefore multimodal therapy strategies, targeting signaling pathways simultaneously should improve treatment.SiRNAs against KRAS and the apoptosis associated genes BCLXL, FLIP, MCL1L, SURVIVIN and XIAP were transfected into human and murine pancreatic cancer cell lines. Induction of apoptosis was measured by Caspase 3/7 activation, subG1 FACS analysis and PARP cleavage. The therapeutic approach was tested in a subcutaneous allograft model with a murine cancer cell line.By using siRNAs as a systematic approach to remodel signal transduction in pancreatic cancer the results showed increasing inhibition of proliferation and apoptosis induction in vitro and in vivo. Thus, siRNAs are suitable to model multimodal therapy against signaling pathways in pancreatic cancer. Improvements in in vivo delivery of siRNAs against a multitude of targets might therefore be a potential therapeutic approach.
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Werner
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Lademann
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: May-Linn
authors.initials: ML
authors.lastname: Thepkaysone
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Jahnke
authors.affiliation: Institute of Pathology, TU Dresden, 01307 Dresden, Germany.
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Weber
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C117307:KRAS protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; C434062:TNIP2 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; RNAi; apoptosis; pancreatic cancer; simultaneous gene silencing