論文 - 詳細
| RRC ID | 27186 |
|---|---|
| 著者 | Cogoi S, Zorzet S, Rapozzi V, Géci I, Pedersen EB, Xodo LE. |
| タイトル | 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. |
| ジャーナル | 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. |
| 巻・号 | 41(7) |
| ページ | 4049-64 |
| 公開日 | 2013-4-1 |
| 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 | 11.502 |
| 引用数 | 55 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| 遺伝子材料 | pCMV-MAZ (RDB03219) pGEX-hMAZ (RDB05701) |