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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / genetics
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Cell Cycle / genetics
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Cell Line, Tumor
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Cell Proliferation / genetics
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Cell Survival / genetics
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gemcitabine
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Humans
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MCF-7 Cells
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MicroRNAs / genetics*
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Mutation / genetics
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Paclitaxel / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins p21(ras) / biosynthesis
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Proto-Oncogene Proteins p21(ras) / genetics*
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Ribonucleoside Diphosphate Reductase / biosynthesis
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Signal Transduction / genetics
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Transfection
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Tubulin / biosynthesis
Substances
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Antineoplastic Agents
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KRAS protein, human
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MicroRNAs
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TUBB3 protein, human
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Tubulin
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mirnlet7 microRNA, human
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Deoxycytidine
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ribonucleotide reductase M2
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Ribonucleoside Diphosphate Reductase
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Proto-Oncogene Proteins p21(ras)
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Paclitaxel
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Gemcitabine