Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer
Cells

J 2017

Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

NEHYBOVÁ, Tereza, Jan ŠMARDA, Lukáš DANIEL, Marek STIBOREK, Viktor KANICKÝ et. al.

Basic information

Original name

Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

Authors

NEHYBOVÁ, Tereza (203 Czech Republic, belonging to the institution), Jan ŠMARDA (203 Czech Republic, belonging to the institution), Lukáš DANIEL (203 Czech Republic, belonging to the institution), Marek STIBOREK (203 Czech Republic, belonging to the institution), Viktor KANICKÝ (203 Czech Republic, belonging to the institution), Ivan SPASOJEVIČ (688 Serbia), Jan PREISLER (203 Czech Republic, belonging to the institution), Jiří DAMBORSKÝ (203 Czech Republic, belonging to the institution) and Petr BENEŠ (203 Czech Republic, belonging to the institution)

Edition

International Journal of Molecular Sciences, Basel, MDPI, 2017, 1422-0067

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.687

RIV identification code

RIV/00216224:14310/17:00094712

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.3390/ijms18040729

UT WoS

000402639400055

Keywords in English

breast cancer; copper; proteasome; reactive oxygen species; wedelolactone

Abstract

V originále

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.

Links

GA15-05387S, research and development project

Name: Laserově desorpční hmotnostní spektrometrie pro analýzu molekul a nanočástic

Investor: Czech Science Foundation

LO1214, research and development project

Name: Centrum pro výzkum toxických látek v prostředí (Acronym: RECETOX)

Investor: Ministry of Education, Youth and Sports of the CR

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/0967/2015, interní kód MU

Name: Podpora výzkumné činnosti studentů molekulární biologie a genetiky 4 (Acronym: MBG4)

Investor: Masaryk University, Category A

Citovat

NEHYBOVÁ, Tereza, Jan ŠMARDA, Lukáš DANIEL, Marek STIBOREK, Viktor KANICKÝ, Ivan SPASOJEVIČ, Jan PREISLER, Jiří DAMBORSKÝ and Petr BENEŠ. Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. International Journal of Molecular Sciences. Basel: MDPI, 2017, vol. 18, No 4, p. nestránkováno, 14 pp. ISSN 1422-0067. Available from: https://dx.doi.org/10.3390/ijms18040729.

@article{1378197,
   author = {Nehybová, Tereza and Šmarda, Jan and Daniel, Lukáš and Stiborek, Marek and Kanický, Viktor and Spasojevič, Ivan and Preisler, Jan and Damborský, Jiří and Beneš, Petr},
   article_location = {Basel},
   article_number = {4},
   doi = {http://dx.doi.org/10.3390/ijms18040729},
   keywords = {breast cancer; copper; proteasome; reactive oxygen species; wedelolactone},
   language = {eng},
   issn = {1422-0067},
   journal = {International Journal of Molecular Sciences},
   title = {Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells},
   url = {http://www.mdpi.com/1422-0067/18/4/729},
   volume = {18},
   year = {2017}
}

TY  - JOUR
ID  - 1378197
AU  - Nehybová, Tereza - Šmarda, Jan - Daniel, Lukáš - Stiborek, Marek - Kanický, Viktor - Spasojevič, Ivan - Preisler, Jan - Damborský, Jiří - Beneš, Petr
PY  - 2017
TI  - Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells
JF  - International Journal of Molecular Sciences
VL  - 18
IS  - 4
SP  - nestránkováno
EP  - nestránkováno
PB  - MDPI
SN  - 14220067
KW  - breast cancer
KW  - copper
KW  - proteasome
KW  - reactive oxygen species
KW  - wedelolactone
UR  - http://www.mdpi.com/1422-0067/18/4/729
L2  - http://www.mdpi.com/1422-0067/18/4/729
N2  - 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.
ER  -

NEHYBOVÁ, Tereza, Jan ŠMARDA, Lukáš DANIEL, Marek STIBOREK, Viktor KANICKÝ, Ivan SPASOJEVIČ, Jan PREISLER, Jiří DAMBORSKÝ and Petr BENEŠ. Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. \textit{International Journal of Molecular Sciences}. Basel: MDPI, 2017, vol.~18, No~4, p.~nestránkováno, 14 pp. ISSN~1422-0067. Available from: https://dx.doi.org/10.3390/ijms18040729.

Detailed Information on Publication Record