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.
Highlights
KRAS mutations occur in approximately 20% of all human cancers and are prevalent in pancreatic ductal adenocarcinoma (PDAC, ~90%), non-small cell lung cancer (NSCLC, ~25%) and colorectal cancer (~40%) [1]
Our study reveals that let-7b repletion selectively downregulates mutant KRAS expression and potentiates the anticancer activity of paclitaxel and gemcitabine in KRAS mutant tumor cells, which is accompanied by attenuated cell proliferation, enhanced apoptosis and the reversal of the epithelial-mesenchymal transition (EMT) phenotype in tumor cells
Resistance to cisplatin in glioblastoma cells has been associated with low let-7b level
Summary
KRAS mutations occur in approximately 20% of all human cancers and are prevalent in pancreatic ductal adenocarcinoma (PDAC, ~90%), non-small cell lung cancer (NSCLC, ~25%) and colorectal cancer (~40%) [1]. Constitutively activated KRAS transduces cascades of parallel phosphorylation reactions in RAF/MEK/ERK and PI3K/AKT/ mTOR pathways among others, culminating with uncontrolled cell proliferation, evasion of apoptosis, and metastasis. Intensive effort has been made to target mutant RAS for the treatment of cancer. A number of strategies have been pursued in order to thwart KRAS-driven oncogenesis, including the combination of kinase inhibitors (such as PI3K and MEK inhibitors) to simultaneously repress downstream RAS effectors [2,3], the inhibitors that directly attenuate the kinase activity of mutant KRAS [4,5], and the small interference RNAs (siRNAs) that knockdown mutant KRAS [6]. Treatment of KRAS mutant tumors still largely relies on conventional chemotherapy, which commonly results in poor response rate and development of drug resistance in cancer patients
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