Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.

Abstract

Pathological post-transcriptional control of the proteome composition is a central feature of malignancy. Two steps in this pathway, eIF4F-driven cap-dependent mRNA translation and the ubiquitin-proteasome system (UPS), are deregulated in most if not all cancers. We tested a hypothesis that eIF4F is aberrantly activated in human esophageal adenocarcinoma (EAC) and requires elevated rates of protein turnover and proteolysis and thereby activated UPS for its pro-neoplastic function. Here, we show that 80% of tumors and cell lines featuring amplified ERBB2 display an aberrantly activated eIF4F. Direct genetic targeting of the eIF4F in ERBB2-amplified EAC cells with a constitutively active form of the eIF4F repressor 4E-BP1 decreased colony formation and proliferation and triggered apoptosis. In contrast, suppression of m-TOR-kinase activity towards 4E-BP1with rapamycin only modestly inhibited eIF4F-driven cap-dependent translation and EAC malignant phenotype; and promoted feedback activation of other cancer pathways. Our data show that co-treatment with 2 FDA-approved agents, the m-TOR inhibitor rapamycin and the proteasome inhibitor bortezomib, leads to strong synergistic growth-inhibitory effects. Moreover, direct targeting of eIF4F with constitutively active 4E-BP1 is significantly more potent in collaboration with bortezomib than rapamycin. These data support the hypothesis that a finely tuned balance between eIF4F-driven protein synthesis and proteasome-mediated protein degradation is required for the maintenance of ERBB2-mediated EAC malignant phenotype. Altogether, our study supports the development of pharmaceuticals to directly target eIF4F as most efficient strategy; and provides a clear rationale for the clinical evaluation of combination therapy with m-TOR inhibitors and bortezomib for EAC treatment.

• Authors: O A Issaenko, P B Bitterman, V A Polunovsky, P S Dahlberg
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 19 Issue 9 Pg. 609-18 (Sep 2012) ISSN: 1476-5500 [Electronic] England
• PMID: 22767218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Boronic Acids
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Eukaryotic Initiation Factor-4F
• Phosphoproteins
• Proteasome Inhibitors
• Pyrazines
• RNA Caps
• RNA, Messenger
• RNA, Small Interfering
• Repressor Proteins
• Ubiquitin
• Bortezomib
• ERBB2 protein, human
• Receptor, ErbB-2
• Proteasome Endopeptidase Complex
• Sirolimus

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Apoptosis
• Boronic Acids (pharmacology)
• Bortezomib
• Case-Control Studies
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Proliferation
• Drug Synergism
• Enzyme Activation
• Esophageal Neoplasms (drug therapy, metabolism, therapy)
• Eukaryotic Initiation Factor-4F (genetics, metabolism)
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Gene Targeting (methods)
• Humans
• Phenotype
• Phosphoproteins (genetics, metabolism)
• Phosphorylation
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Proteasome Inhibitors (pharmacology)
• Protein Biosynthesis
• Proteolysis
• Pyrazines (pharmacology)
• RNA Caps (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Sirolimus (pharmacology)
• Ubiquitin (genetics, metabolism)