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Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

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2017
1045.pdf (4.564Mb)
Authors
Nehybova, Tereza
Smarda, Jan
Daniel, Lukas
Stiborek, Marek
Kanicky, Viktor
Spasojević, Ivan
Preisler, Jan
Damborsky, Jiri
Benes, Petr
Article (Published version)
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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 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 cancer
Source:
International Journal of Molecular Sciences, 2017, 18, 4
Publisher:
  • 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
[ Google Scholar ]
19
6
URI
http://rimsi.imsi.bg.ac.rs/handle/123456789/1048
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Institut za multidisciplinarna istraživanja
TY  - 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 . .

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