Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

2017
Authors
Nehybova, TerezaSmarda, Jan
Daniel, Lukas

Stiborek, Marek
Kanicky, Viktor
Spasojević, Ivan

Preisler, Jan

Damborsky, Jiri

Benes, Petr

Article (Published version)
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Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxi...city of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.
Keywords:
wedelolactone / reactive oxygen species / proteasome / copper / breast cancerSource:
International Journal of Molecular Sciences, 2017, 18, 4Publisher:
- MDPI, Basel
Funding / projects:
- National Program of Sustainability II (MEYS CR) [LQ1601, LQ1605, LO1214]
- Czech Science FoundationGrant Agency of the Czech Republic [15-05387S]
- Masaryk University [MUNI/A/0967/2015]
DOI: 10.3390/ijms18040729
ISSN: 1422-0067
PubMed: 28353647
WoS: 000402639400055
Scopus: 2-s2.0-85016578316
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Institution/Community
Institut za multidisciplinarna istraživanjaTY - JOUR AU - Nehybova, Tereza AU - Smarda, Jan AU - Daniel, Lukas AU - Stiborek, Marek AU - Kanicky, Viktor AU - Spasojević, Ivan AU - Preisler, Jan AU - Damborsky, Jiri AU - Benes, Petr PY - 2017 UR - http://rimsi.imsi.bg.ac.rs/handle/123456789/1048 AB - Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells. PB - MDPI, Basel T2 - International Journal of Molecular Sciences T1 - Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells IS - 4 VL - 18 DO - 10.3390/ijms18040729 ER -
@article{ author = "Nehybova, Tereza and Smarda, Jan and Daniel, Lukas and Stiborek, Marek and Kanicky, Viktor and Spasojević, Ivan and Preisler, Jan and Damborsky, Jiri and Benes, Petr", year = "2017", abstract = "Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.", publisher = "MDPI, Basel", journal = "International Journal of Molecular Sciences", title = "Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells", number = "4", volume = "18", doi = "10.3390/ijms18040729" }
Nehybova, T., Smarda, J., Daniel, L., Stiborek, M., Kanicky, V., Spasojević, I., Preisler, J., Damborsky, J.,& Benes, P.. (2017). Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. in International Journal of Molecular Sciences MDPI, Basel., 18(4). https://doi.org/10.3390/ijms18040729
Nehybova T, Smarda J, Daniel L, Stiborek M, Kanicky V, Spasojević I, Preisler J, Damborsky J, Benes P. Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. in International Journal of Molecular Sciences. 2017;18(4). doi:10.3390/ijms18040729 .
Nehybova, Tereza, Smarda, Jan, Daniel, Lukas, Stiborek, Marek, Kanicky, Viktor, Spasojević, Ivan, Preisler, Jan, Damborsky, Jiri, Benes, Petr, "Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells" in International Journal of Molecular Sciences, 18, no. 4 (2017), https://doi.org/10.3390/ijms18040729 . .