ABSTRACT
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 PI3Kî²AKT, and not by MEKî²ERK1/2, signaling. We also show that activation of the mammalian target of rapamycin complex 1 (mTORC1)î²ribosomal 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 PI3Kî²AKT 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 PI3Kî²AKT 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 PI3Kî²AKT 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.
Subject(s)
Eukaryotic Initiation Factor-4A/physiology , Mucin-1/biosynthesis , Protein Biosynthesis , Protein Subunits/biosynthesis , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Proliferation , Down-Regulation , Epidermal Growth Factor/physiology , ErbB Receptors/metabolism , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Gene Expression , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mucin-1/genetics , Neuregulin-1/physiology , Phosphatidylinositol 3-Kinases/metabolism , Protein Subunits/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Triterpenes/pharmacologyABSTRACT
Guarana (Paullinia cupana var. sorbilis) is a plant native to the central Amazon basin. Roasted seed extracts have been used as medicinal beverages since pre-Colombian times, due to their reputation as stimulants, aphrodisiacs, tonics, as well as protectors of the gastrointestinal tract. Guarana plants are commercially cultivated exclusively in Brazil to supply the national carbonated soft-drink industry and natural product stores around the world. In this report, we describe and discuss the annotation of 15,387 ESTs from guarana seeded-fruits, highlighting sequences from the flavonoid and purine alkaloid pathways, and those related to biotic stress avoidance. This is the largest set of sequences registered for the Sapindaceae family.
