title: Let-7 Sensitizes KRAS Mutant Tumor Cells to Chemotherapy.
abstract: KRAS is the most commonly mutated oncogene in human cancers and is associated with poor prognosis and drug resistance. Let-7 is a family of tumor suppressor microRNAs that are frequently suppressed in solid tumors, where KRAS mutations are highly prevalent. In this study, we investigated the potential use of let-7 as a chemosensitizer. We found that let-7b repletion selectively sensitized KRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type KRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEK/ERK and PI3K/AKT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in KRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of β-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of KRAS mutant tumors.
authors.affiliation: Department of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, United States of America.
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D014404:Tubulin / Q000096:biosynthesis; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D035683:MicroRNAs; C498585:TUBB3 protein, human; D014404:Tubulin; C487931:mirnlet7 microRNA, human; D003841:Deoxycytidine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D017239:Paclitaxel; D000093542:Gemcitabine