Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein.
The oncogenic MUC1 C-terminal subunit (MUC1-C) subunit is aberrantly overexpressed in most human breast cancers by mechanisms that are not well understood. The present studies demonstrate that stimulation of non-malignant MCF-10A cells with epidermal growth factor (EGF) or heregulin (HRG) results in marked upregulation of MUC1-C translation. Growth factor-induced MUC1-C translation was found to be mediated by PI3KAKT, and not by MEKERK1/2, signaling. We also show that activation of the mammalian target of rapamycin complex 1 (mTORC1)ribosomal protein S6 kinase 1 (S6K1) pathway decreases tumor suppressor programmed cell death protein 4 (PDCD4), an inhibitor of the eIF4A RNA helicase, and contributes to the induction of MUC1-C translation. In concert with these results, treatment of growth factor-stimulated MCF-10A cells with the eIF4A RNA helicase inhibitors, silvestrol and CR-1-31-B, blocked increases in MUC1-C abundance. The functional significance of the increase in MUC1-C translation is supported by the demonstration that MUC1-C, in turn, forms complexes with EGF receptor (EGFR) and promotes EGFR-mediated activation of the PI3KAKT pathway and the induction of growth. Compared with MCF-10A cells, constitutive overexpression of MUC1-C in breast cancer cells was unaffected by EGF stimulation, but was blocked by inhibiting PI3KAKT signaling. The overexpression of MUC1-C in breast cancer cells was also inhibited by blocking eIF4A RNA helicase activity with silvestrol and CR-1-31-B. These findings indicate that EGF-induced MUC1-C expression is mediated by the PI3KAKT pathway and the eIF4A RNA helicase, and that this response promotes EGFR signaling in an autoinductive loop. The findings also indicate that targeting the eIF4A RNA helicase is a novel approach for blocking MUC1-C overexpression in breast cancer cells.
Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
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D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D018396:Mucin-1 / Q000096:biosynthesis* / Q000235:genetics; D020890:Neuregulin-1 / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
D051017:Apoptosis Regulatory Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D039601:Eukaryotic Initiation Factor-4A; D018396:Mucin-1; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; C060192:MUC1 protein, human; C114487:PDCD4 protein, human; C489897:silvestrol; D001572:Benzofurans; C546842:MTOR protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1