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c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

Oncogene volume 33, pages 4508–4520 (2014)Cite this article

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Abstract

Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.

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Acknowledgements

We thank the following individuals for their assistance. Garretson Epperly and James Begley (confocal), Spear/Peterson Labs (qPCR), Jonathan Sims and Divya Srinivasan (cell lysates), Vivek Rangnekar, Suzanne Ridges, Aditi Jain (manuscript review) and Woodrow Friend (Figures 1a and 6d). Mass spectrometry was performed at the University of Kentucky Proteomics Core Facility, which is supported in part by the Office of the Vice President for Research. Edman Degradation was performed at the University of Nebraska Protein Structure Core Facility. This work was supported by NIH/NCI/R01 grants to RP (CA116784, CA166499). Dr Plattner is funded by NIH/NCI. DMK also is funded by NIH/NCI, but this work was not supported by his grants.

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Author notes

  1. J R McCorkle

    Present address: 7Current Address: Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.,

  2. L S Fiore and S S Ganguly: These authors contributed equally to this work and are listed in alphabetical order.

Authors and Affiliations

  1. Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, KY, USA

    L S Fiore, S S Ganguly, J Sledziona, J R McCorkle & R Plattner

  2. Department of Pathology, University of Kentucky School of Medicine, Lexington, KY, USA

    M L Cibull, D L Richards & J M Neltner

  3. Department of Biostatistics and Markey Cancer Center, University of Kentucky School of Medicine, Lexington, KY, USA

    C Wang

  4. Department of Biochemistry, University of Kentucky School of Medicine, Lexington, KY, USA

    C Beach

  5. Department of Molecular and Cellular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    D M Kaetzel

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  1. L S Fiore
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Author contributions

LSF performed experiments for Figures 2 and SSG performed experiments for Figures 3, 4 and 6. LSF and SSG equally contributed data in Figure 1. JS assisted with experiments performed in Figure 2. Pathologists MLS, DLR and JMN blindly scored primary tumors. CW performed statistics. CB performed mass spectrometry. JRM made NM23-H1 constructs and lentiviral stocks. DMK was involved in the experimental planning and design. RP directed the project and wrote the manuscript.

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Fiore, L., Ganguly, S., Sledziona, J. et al. c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene 33, 4508–4520 (2014). https://doi.org/10.1038/onc.2013.399

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