Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein.

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 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.

• Authors: C Jin, H Rajabi, C M Rodrigo, J A Porco Jr, D Kufe
• Journal: Oncogene (Oncogene) Vol. 32 Issue 17 Pg. 2179-88 (Apr 25 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 22689062 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• MUC1 protein, human
• Mucin-1
• Neuregulin-1
• PDCD4 protein, human
• Protein Subunits
• RNA-Binding Proteins
• Triterpenes
• silvestrol
• Epidermal Growth Factor
• MTOR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• ribosomal protein S6 kinase, 70kD, polypeptide 1
• Eukaryotic Initiation Factor-4A

Topics

• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cell Proliferation
• Down-Regulation
• Epidermal Growth Factor (physiology)
• ErbB Receptors (metabolism)
• Eukaryotic Initiation Factor-4A (antagonists & inhibitors, physiology)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Mucin-1 (biosynthesis, genetics)
• Neuregulin-1 (physiology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Biosynthesis
• Protein Subunits (biosynthesis, genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Triterpenes (pharmacology)