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

Cancer Gene Therapy volume 19, pages 609–618 (2012)Cite this article

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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.

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Acknowledgements

We are indebted to Dr Zofia Zukowska, Department of Integrative Biology and Physiology, University of Minnesota for the encouragement, tremendous support and providing the possibility to complete this work. We would like to acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, University of Minnesota, supported in part by P30 CA77598.

Grant and Financial Support: This work was supported by VFW Surgical Oncology Award, American Cancer Society IRG and Minnesota Medical Foundation to P.S.D.

Ethics statement: The study complied with the Declaration of Helsinki. Normal and malignant (adenocarcinoma) esophageal tissue samples (n=12) were obtained from the Cooperative Human Tissue Network and from the clinical esophageal cancer practice approved by the University of Minnesota Institutional Review Board. All patients gave written informed consent before surgery.

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  1. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    O A Issaenko & P S Dahlberg

  2. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    O A Issaenko, P B Bitterman, V A Polunovsky & P S Dahlberg

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  1. O A Issaenko
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Correspondence to O A Issaenko.

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Issaenko, O., Bitterman, P., Polunovsky, V. et al. Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype. Cancer Gene Ther 19, 609–618 (2012). https://doi.org/10.1038/cgt.2012.39

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