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: Xin Dai, Ying Jiang, Chalet Tan
• Journal: PloS one (PLoS One) Vol. 10 Issue 5 Pg. e0126653 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25946136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• MicroRNAs
• TUBB3 protein, human
• Tubulin
• mirnlet7 microRNA, human
• Deoxycytidine
• ribonucleotide reductase M2
• Ribonucleoside Diphosphate Reductase
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Proto-Oncogene Proteins p21(ras)
• Paclitaxel
• Gemcitabine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (genetics)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cell Survival (genetics)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• MCF-7 Cells
• MicroRNAs (genetics)
• Mutation (genetics)
• Neoplasms (drug therapy, genetics)
• Paclitaxel (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins p21(ras) (biosynthesis, genetics)
• Ribonucleoside Diphosphate Reductase (biosynthesis)
• Signal Transduction (genetics)
• Transfection
• Tubulin (biosynthesis)
• Gemcitabine