Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

Kyung Min Yang, Eunjin Bae, Sung Gwe Ahn, Kyoungwha Pang, Yuna Park, Jinah Park, Jihee Lee, Akira Ooshima, Bora Park, Junil Kim, Yunshin Jung, Satoru Takahashi, Joon Jeong, Seok Hee Park, Seong Jin Kim

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17 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer. The mechanisms controlling the pro- and anti-oncogenic roles of cathepsin B are unclear. Yang et al. find that BAG2 is a regulator of the dual functions of its client protein, CTSB, facilitating the progression of TNBC.

Original languageEnglish
Pages (from-to)2952-2964
Number of pages13
JournalCell Reports
Volume21
Issue number10
DOIs
Publication statusPublished - 2017 Dec 5

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yang, K. M., Bae, E., Ahn, S. G., Pang, K., Park, Y., Park, J., Lee, J., Ooshima, A., Park, B., Kim, J., Jung, Y., Takahashi, S., Jeong, J., Park, S. H., & Kim, S. J. (2017). Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells. Cell Reports, 21(10), 2952-2964. https://doi.org/10.1016/j.celrep.2017.11.026