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Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis

Oncogene volume 32, pages 3829–3839 (2013)Cite this article

Abstract

We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF-1α protein allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro-angiogenic pathways and recruitment of bone marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer.

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Acknowledgements

This work was supported by National Institute of Health grants CA92440 grant to MMM and R01CA118399 to AAE. WK was supported by a Scholarship for the Development of New Faculty Staff from the Chulalongkorn University in Thailand. The HPLC-MS-MS instrument used for HMBA analysis was funded by National Science Foundation MRI grant (CHE-0923308) to YX. KS is supported by a US Department of Education GAANN grant (P200A070595-08) to YX.

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Author notes

  1. B M Wittmann

    Present address: 7Current address: Metabolon Inc., Durham, NC 27713, USA,

Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University Cleveland, Cleveland, OH, USA

    W Ketchart, B M Wittmann, Y Hu, Y Q Doughman & M M Montano

  2. Department of Chemistry, Cleveland State University, Cleveland, OH, USA

    K M Smith & Y Xu

  3. Department of Radiology, Case Western Reserve University Cleveland, Cleveland, OH, USA

    T Krupka & A A Exner

  4. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    P A Rayman & J H Finke

  5. Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, Cleveland, OH, USA

    J M Albert

  6. Center for RNA Molecular Biology, Case Western Reserve University Cleveland, Cleveland, OH, USA

    X Bai

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Ketchart, W., Smith, K., Krupka, T. et al. Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis. Oncogene 32, 3829–3839 (2013). https://doi.org/10.1038/onc.2012.405

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