Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy

Oncotarget. 2016 Jan 26;7(4):3984-92. doi: 10.18632/oncotarget.6766.

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.

Keywords: KRAS; RNAi; apoptosis; pancreatic cancer; simultaneous gene silencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Female
  • Gene Silencing*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survivin
  • Tumor Cells, Cultured
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BCL2L1 protein, human
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • KRAS protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • RNA, Messenger
  • RNA, Small Interfering
  • Survivin
  • TNIP2 protein, human
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • bcl-X Protein
  • Proto-Oncogene Proteins p21(ras)