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

L. S. Fiore, S. S. Ganguly, J. Sledziona, M. L. Cibull, C. Wang, D. L. Richards, J. M. Neltner, C. Beach, J. R. McCorkle, D. M. Kaetzel, R. Plattner

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish
Pages (from-to)4508-4520
Number of pages13
Issue number36
StatePublished - Sep 4 2014

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2014 Macmillan Publishers Limited All rights reserved.


  • Arg
  • NM23-H1
  • c-Abl
  • cathepsin
  • metastasis suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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