Impairment of K‐Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR‐143

• DOI: 10.1111/cas.13559
• Publication Date: 2018-03-02T14:12:40Z
• Authors: Yukihiro Akao; Minami Kumazaki; Haruka Shinohara; Nobuhiko Sugito; Yuki Kuranaga; Takuya Tsujino; Yuki Yoshikawa; Yukio Kitade
• Keywords: Flavonoids; 0301 basic medicine; 0303 health sciences; Cell Survival; Drug Synergism; Original Articles; Proto-Oncogene Proteins p21(ras); Mice; MicroRNAs; 03 medical and health sciences; Cell Line, Tumor; Colonic Neoplasms; Mutation; Animals; Humans; Benzimidazoles; Benzothiazoles; HT29 Cells; Protein Kinase Inhibitors; Neoplasm Transplantation; Cell Proliferation; Signal Transduction

Despite considerable research on K‐Ras inhibitors, none had been established until now. We synthesized nuclease‐resistant synthetic miR‐143 (miR‐143#12), which strongly silenced K‐Ras, its effector signal molecules AKT and ERK, the activator Sos1. examined anti‐proliferative effect of miR‐143#12 mechanism in human colon cancer DLD‐1 cell (G13D) other types harboring mutations. Cell growth was markedly suppressed a concentration‐dependent manner by (IC 50 : 1.32 nmol L −1 ) with decrease mRNA level. Interestingly, this level also downregulated either PI3K/AKT or MEK inhibitor, indicates positive circuit expression. MiR‐143#12 cytoplasmic expression impaired directly targeting ERK mRNA. Combination treatment low‐dose EGFR inhibitor induced synergistic inhibition marked inactivation both MAPK/ERK signaling pathways. However, silencing siR‐KRas instead did not induce synergism through combined inhibitor. Thus, perturbed system activation Sos1 and, resultantly, restored efficacy inhibitors. The vivo results supported those vitro experiments. extremely potent enabled us to understand networks shut them down combination miRNA K‐Ras‐driven lines.