Abstract
Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Carcinoma, Non-Small-Cell Lung / genetics*
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Down-Regulation
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Drug Resistance, Neoplasm / genetics
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Epithelial-Mesenchymal Transition / genetics*
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Gene Expression Regulation, Neoplastic
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Heterografts
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Homeodomain Proteins / biosynthesis
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Humans
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Lung Neoplasms / genetics*
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MAP Kinase Kinase 1 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics
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Mucin-1 / biosynthesis
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Mucin-1 / genetics*
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Neoplasm Transplantation
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Oxadiazoles / pharmacology
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Peptides / pharmacology
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins p21(ras)
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RNA Interference
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RNA, Small Interfering
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Signal Transduction / drug effects
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Spheroids, Cellular
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Transcription Factors / biosynthesis
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Tumor Cells, Cultured
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Zinc Finger E-box-Binding Homeobox 1
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ras Proteins / genetics*
Substances
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(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine
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GSK690693
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Homeodomain Proteins
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KRAS protein, human
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MIRN200 microRNA, human
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MUC1 protein, human
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MicroRNAs
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Mucin-1
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Oxadiazoles
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Peptides
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Transcription Factors
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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Proto-Oncogene Proteins c-akt
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MAP Kinase Kinase 1
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Proto-Oncogene Proteins p21(ras)
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ras Proteins