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, Jeong Joon, Seok Hee Park, Seong Jin Kim

Research output: Contribution to journalArticle

7 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

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Triple Negative Breast Neoplasms
Cathepsin B
Cells
Neoplasm Metastasis
Annexin A2
Biomarkers
Carcinogenesis
Apoptosis
Breast Neoplasms
Lung
Enzymes
Therapeutics
Processing

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, K. M., Bae, E., Ahn, S. G., Pang, K., Park, Y., Park, J., ... 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
Yang, Kyung Min ; Bae, Eunjin ; Ahn, Sung Gwe ; Pang, Kyoungwha ; Park, Yuna ; Park, Jinah ; Lee, Jihee ; Ooshima, Akira ; Park, Bora ; Kim, Junil ; Jung, Yunshin ; Takahashi, Satoru ; Joon, Jeong ; Park, Seok Hee ; Kim, Seong Jin. / Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells. In: Cell Reports. 2017 ; Vol. 21, No. 10. pp. 2952-2964.
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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.",
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Yang, KM, Bae, E, Ahn, SG, Pang, K, Park, Y, Park, J, Lee, J, Ooshima, A, Park, B, Kim, J, Jung, Y, Takahashi, S, Joon, J, Park, SH & Kim, SJ 2017, 'Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells', Cell Reports, vol. 21, no. 10, pp. 2952-2964. https://doi.org/10.1016/j.celrep.2017.11.026

Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells. / Yang, Kyung Min; Bae, Eunjin; Ahn, Sung Gwe; Pang, Kyoungwha; Park, Yuna; Park, Jinah; Lee, Jihee; Ooshima, Akira; Park, Bora; Kim, Junil; Jung, Yunshin; Takahashi, Satoru; Joon, Jeong; Park, Seok Hee; Kim, Seong Jin.

In: Cell Reports, Vol. 21, No. 10, 05.12.2017, p. 2952-2964.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

AU - Yang, Kyung Min

AU - Bae, Eunjin

AU - Ahn, Sung Gwe

AU - Pang, Kyoungwha

AU - Park, Yuna

AU - Park, Jinah

AU - Lee, Jihee

AU - Ooshima, Akira

AU - Park, Bora

AU - Kim, Junil

AU - Jung, Yunshin

AU - Takahashi, Satoru

AU - Joon, Jeong

AU - Park, Seok Hee

AU - Kim, Seong Jin

PY - 2017/12/5

Y1 - 2017/12/5

N2 - 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.

AB - 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.

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