PMID:28334682

Citation	Lewinska, A, Bednarz, D, Adamczyk-Grochala, J and Wnuk, M (2017) Phytochemical-induced nucleolar stress results in the inhibition of breast cancer cell proliferation. Redox Biol 12:469-482
Abstract	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.
Links	PubMed PMC5362140 Online version:10.1016/j.redox.2017.03.014
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ACTB		GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Paper’s Protein Name: β-actin. UniProt Protein Name: Actin, cytoplasmic 1 or Beta-actin. Notes: Figure 3F is used. MCF-7 cells (which are human) have their nuclei stained blue and are also immunostained so that β-actin will appear green. As can be seen in the micrographs, there is significant overlap between these colors. Thus a non-transient link is established between β-actin and the nucleus.	complete CACAO 12740
HUMAN:LMNA		GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Paper’s Protein Name: Lamin A/C. UniProt’s Protein Name: Prelamin-A/C. (According to UniProt, this is cleaved into the chain Lamin A/C. Regardless, the official location of Lamin A/C on UniProt is this page.) Notes: Figure 4B is used. MCF-7 cells (which are human) have their nuclei stained blue and are also immunostained so that Lamin A/C will appear green. As can be seen in the micrographs, there is significant overlap of these colors. While Lamin A/C appears to be more vividly colored when the cells are exposed to sulforaphane, it nevertheless can be seen even in the control. Therefore, a non-transient link is established between Lamin A/C and the nucleus.	complete CACAO 12748
HUMAN:CDN1A	Colocalizes with	GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Paper’s Protein Name: “p21, a cell cycle inhibitor.” UniProt Protein Name: Cyclin-dependent kinase inhibitor 1 OR p21. Notes: Figure 1D is used. Normal human mammary epithelial cells (HMEC) and MCF-7 human cancer cells are stained with Hoechst 33342 to make the nuclei appear blue. They are also immunostained so that p21 will appear green. As can be seen in the micrographs, p21 only is present in the cancer cells, and only when they are treated with Phytochemicals. Thus, a link is established between p21 and the nucleus, but it is a transient relationship.	complete CACAO 12737
HUMAN:LMNB1		GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Protein Name: Lamin B1. Notes: Figure 4G is used. MCF-7 cells (which are human) have their nuclei stained blue and are also immunostained so that Lamin B1 will appear green. As can be seen in the micrograph control groups, there is significant overlap of these colors. There thus appears to be a non-transient link between Lamin B1 and the nucleus.	complete CACAO 12750
HUMAN:KI67		GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Protein Name: Proliferation marker protein Ki-67. Notes: Figure 1D is used. Normal human mammary epithelial cells (HMEC) are stained with Hoechst 33342 to make the nuclei appear blue. They are also immunostained so that Ki67 will appear green. As can be seen in the bottom row, the Ki67 protein is present in the nucleus for HMEC cells whether they are treated with Phytochemicals or not. Thus, Ki67 is linked to the nucleus, in a non-transient manner.	complete CACAO 12736
HUMAN:COF1	Colocalizes with	GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Protein Name: Cofilin. Notes: Figure 3G is used. MCF-7 cells (which are human) have their nuclei stained blue and are also immunostained so that cofilin will appear red. As can be seen in the micrographs, cofilin does not have overlap with the nuclei until the cells are exposed to sulforaphane. Thus, a link is established between cofilin and the nucleus, but it is a transient relationship.	complete CACAO 12741
HUMAN:RRN3		GO:0005730: nucleolus	ECO:0000314:		C		Organism: Homo sapiens. Protein Name: RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA. Notes: Figure 6B is used. MCF-7 cells (which are human) have their nucleoli stained red and are also immunostained so that RRN3 will appear green. As can be seen in the micrograph control groups, there is significant overlap of these colors. There thus appears to be a non-transient link between RRN3 and the nucleolus.	complete CACAO 12752
HUMAN:RRN3		GO:0005634: nucleus	ECO:0000314:		C		Organism: Homo sapiens. Protein Name: RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA. Notes: Figure 6B is used. MCF-7 cells (which are human) have their nuclei stained blue and are also immunostained so that RRN3 will appear green. As can be seen in the micrograph control groups, there is significant overlap of these colors. There thus appears to be a non-transient link between RRN3 and the nucleus.	complete CACAO 12753

References

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