Phytochemical-induced nucleolar stress results in the inhibition of breast cancer cell proliferation.
The nucleolus is a stress sensor and compromised nucleolar activity may be considered as an attractive anticancer strategy. In the present study, the effects of three plant-derived natural compounds, i.e., sulforaphane (SFN), ursolic acid (UA) and betulinic acid (BA) on nucleolar state were investigated in breast cancer cell lines of different receptor status, namely MCF-7, MDA-MB-231 and SK-BR-3 cells. Cytostatic action of phytochemicals against breast cancer cells was observed at low micromolar concentration window (5-20µM) and mediated by elevated p21 levels, and cell proliferation of SFN-, UA- and BA-treated normal human mammary epithelial cells (HMEC) was unaffected. Phytochemical-mediated inhibition of cell proliferation was accompanied by increased levels of superoxide and protein carbonylation that lead to disorganization of A- and B-type lamin networks and alterations in the nuclear architecture. Phytochemicals promoted nucleolar stress as judged by the nucleoplasmic translocation of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA, inhibition of new rRNA synthesis and decrease in number of nucleoli. Phytochemicals also decreased the levels of NOP2, proliferation-associated nucleolar protein p120, and WDR12 required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome, and phosphorylation of S6 ribosomal protein that may result in diminished translation and inhibition of cell proliferation. In summary, three novel ribotoxic stress stimuli were revealed with a potential to be used in nucleolus-focused anticancer therapy.
Laboratory of Cell Biology, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland. Electronic address: alewinska@o2.pl.
Anna
A
Lewinska
Laboratory of Cell Biology, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
Diana
D
Bednarz
Laboratory of Cell Biology, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
Jagoda
J
Adamczyk-Grochala
Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
Maciej
M
Wnuk
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D061986:MCF-7 Cells; D053978:Pentacyclic Triterpenes; D050050:Protein Carbonylation / Q000187:drug effects; D013454:Sulfoxides; D013481:Superoxides / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology; D000094062:Betulinic Acid; D000097245:Ursolic Acid
D000972:Antineoplastic Agents, Phytogenic; D017879:Isothiocyanates; D053978:Pentacyclic Triterpenes; D013454:Sulfoxides; D013481:Superoxides; D014315:Triterpenes; D000094062:Betulinic Acid; D000097245:Ursolic Acid; C016766:sulforaphane
Breast cancer cells; Cell proliferation; Nucleolus; Pentacyclic triterpenotids; Protein carbonylation; Sulforaphane