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

Oncogene volume 32, pages 2179–2188 (2013)Cite this article

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A Correction to this article was published on 13 April 2021

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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.

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Abbreviations

MUC1:

mucin 1

MUC1-C:

MUC1 C-terminal subunit

EGF:

epidermal growth factor

HRG:

heregulin

mTORC1:

mammalian target of rapamycin complex 1

S6K1:

ribosomal protein S6 kinase 1

PDCD4:

tumor suppressor programmed cell death protein 4.

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Acknowledgements

This work was supported by the National Cancer Institute Grants CA97098, CA42802 and CA100707; the National Institutes of Health Grant GM-073855 (JAP), and a postdoctoral fellowship from the American Cancer Society PF-11-077-01-CDD (CMR).

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Authors and Affiliations

  1. Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

    C Jin, H Rajabi & D Kufe

  2. Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, MA, USA

    C M Rodrigo & J A Porco Jr

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  1. C Jin
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Correspondence to D Kufe.

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DK holds equity in Genus Oncology and is a consultant to the company. The other authors declare no conflict of interest.

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Jin, C., Rajabi, H., Rodrigo, C. et al. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene 32, 2179–2188 (2013). https://doi.org/10.1038/onc.2012.236

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