ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Kim, E; Kim, Y-J; Ji, Z; Kang, JM; Wirianto, M; Paudel, KR; Smith, JA; Ono, K; Kim, J-A; Eckel-Mahan, K; Zhou, X; Lee, HK; Yoo, JY; Yoo, S-H; Chen, Z

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Kim, E Kim, Y-J Ji, Z Kang, JM Wirianto, M Paudel, KR Smith, JA Ono, K Kim, J-A Eckel-Mahan, K Zhou, X Lee, HK Yoo, JY Yoo, S-H Chen, Z

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Publisher:: Springer Science and Business Media LLC
Publication Type:: Journal Article
Citation:: Cell Death & Disease, 2022, 13, (4)
Issue Date:: 2022-04

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Field	Value	Language
dc.contributor.author	Kim, E
dc.contributor.author	Kim, Y-J
dc.contributor.author	Ji, Z
dc.contributor.author	Kang, JM
dc.contributor.author	Wirianto, M
dc.contributor.author	Paudel, KR
dc.contributor.author	Smith, JA
dc.contributor.author	Ono, K
dc.contributor.author	Kim, J-A
dc.contributor.author	Eckel-Mahan, K
dc.contributor.author	Zhou, X
dc.contributor.author	Lee, HK
dc.contributor.author	Yoo, JY
dc.contributor.author	Yoo, S-H
dc.contributor.author	Chen, Z
dc.date.accessioned	2022-04-20T01:29:14Z
dc.date.available	2022-04-20T01:29:14Z
dc.date.issued	2022-04
dc.identifier.citation	Cell Death & Disease, 2022, 13, (4)
dc.identifier.issn	2041-4889
dc.identifier.uri	http://hdl.handle.net/10453/156489
dc.description.abstract	<jats:title>Abstract</jats:title><jats:p>Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.</jats:p>
dc.language	en
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartof	Cell Death & Disease
dc.relation.isbasedon	10.1038/s41419-022-04826-5
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
dc.title	ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer
dc.type	Journal Article
utslib.citation.volume	13
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.date.updated	2022-04-20T01:28:15Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	13
utslib.citation.issue	4

Abstract:

AbstractTriple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.

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