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β-catenin is dynamically stored and cleared in multiple myeloma by the proteasome–aggresome–autophagosome–lysosome pathway

Leukemia volume 26, pages 1116–1119 (2012)Cite this article

Multiple myeloma (MM) is a malignant proliferation of plasma cells (PCs) in the bone marrow (BM). Activation of the canonical WNT/β-catenin signaling pathway is a frequent event in MM;1, 2, 3, 4 however, the molecular mechanisms underlying this phenomenon remain unknown. In contrast to most epithelial cancers, MM lacks mutations in critical components of this pathway, suggesting that deregulated post-translational mechanisms contribute to the aberrant expression of WNT pathway proteins.1, 5 We and others have documented the overexpression of the central WNT signaling molecule, β-catenin, in a majority of MM PCs as compared with normal PCs.1, 2, 3, 6, 7 Post-translational regulation of β-catenin is typically mediated through phosphorylation events that tag the protein for ubiquitination and degradation through the 26S proteasome. In most cellular contexts, the ubiquitin–proteasome system (UPS) is sufficient to handle normal protein synthesis, misfolding and turnover;8 however, exceeding the capacity of the UPS causes polypeptides to accumulate in cytosolic aggregates near the perinuclear microtubule organizing center. Continued stress on the UPS causes additional protein aggregates to amass, forming a dense structural assembly termed the aggresome.9 Aggresomes recruit additional protein catabolic machinery to aid in the unfolding of compacted proteins for proteasomal or autophagosomal/lysosomal removal.10 Thus, aggresome formation provides a reserve protein processing unit to the proteasome to eliminate unwanted proteins.

We suspected that β-catenin could be used as a marker of aggresomes to identify malignant PCs in patient samples. We therefore evaluated the staining pattern in MM paraffin-embedded biopsies using two different antibodies that recognize distinct epitopes of β-catenin. In accordance with the IHC and SEM findings described above, use of either β-catenin antibody revealed a strong perinuclear signal (Supplementary Figure 2). The occurrence of aggresomes in MM cells was also verified with aggresomal markers ubiquitin and vimentin (Supplementary Figure 3); however, we found β-catenin to be a more reliable marker for aggresomes in IHC. We expanded our analysis to include normal (n=20) and MM BM biopsies (n=90) using tissue microarrays; PCs were identified with an anti-CD138 antibody. In all normal samples, β-catenin expression in PCs was barely, if at all, detectable (Figure 1f). Strikingly, greater than 90% of MM cases showed aggresomal β-catenin and nearly all MM cells contained aggresomes (Figure 1f and Supplementary Figure 4). Thus, our data show that aggresomal β-catenin expression is nearly universal in MM, but absent from normal PCs, which highlights its potential use as a biomarker for malignant PCs.

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Acknowledgements

DRC is supported by R01CA151391-01, the Multiple Myeloma Research Foundation, and is a Sidney Kimmel Foundation Scholar.

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Authors and Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA

    K Sukhdeo

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    M Mani, T Hideshima, K Takada, V Pena-Cruz, K C Anderson & D R Carrasco

  3. Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    T Hideshima & K C Anderson

  4. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

    G Mendez & D R Carrasco

  5. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    S Ito

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Sukhdeo, K., Mani, M., Hideshima, T. et al. β-catenin is dynamically stored and cleared in multiple myeloma by the proteasome–aggresome–autophagosome–lysosome pathway. Leukemia 26, 1116–1119 (2012). https://doi.org/10.1038/leu.2011.303

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