RRC ID 27186
Author Cogoi S, Zorzet S, Rapozzi V, Géci I, Pedersen EB, Xodo LE.
Title MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice.
Journal Nucleic Acids Res.
Abstract KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3'-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan-Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy.
Volume 41(7)
Pages 4049-64
Published 2013-4
DOI 10.1093/nar/gkt127
PII gkt127
PMID 23471001
PMC PMC3627599
MeSH Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Apoptosis Binding Sites Binding, Competitive Cell Line, Tumor DNA / chemistry DNA-Binding Proteins / metabolism* G-Quadruplexes Humans Mice Mice, SCID Oligonucleotides / chemistry Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / genetics Pancreatic Neoplasms / pathology Promoter Regions, Genetic Proto-Oncogene Proteins / antagonists & inhibitors* Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins p21(ras) Transcription Factors / metabolism* Transcriptional Activation ras Proteins / antagonists & inhibitors* ras Proteins / genetics ras Proteins / metabolism
IF 11.147
Times Cited 55
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material pCMV-MAZ (RDB03219) pGEX-hMAZ (RDB05701)