Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells
- 472 Downloads
Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells—stressed cells that accumulate with age in mammals—display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.
KeywordsFlavonoids Human fibroblasts Proliferation Invasion IL-6 IL-1A IRAK1/4 NF-κB
We thank Dr. Remi-Martin Laberge for comments and discussions. This work was supported by the SENS Research Foundation to KP and by NIH grants AG009909 and AG017242 to JC.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith OM, Peacocke M, Campisi J (1995) A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367CrossRefPubMedPubMedCentralGoogle Scholar
- Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature Cell Biol 17:1049–1061CrossRefPubMedPubMedCentralGoogle Scholar
- Laberge RM, Zhou L, Sarantos MR, Rodier F, Freund A, de Keizer PL, Liu S, Demaria M, Cong YS, Kapahi P, Desprez PY, Hughes RE, Campisi J (2012a) Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 11:569–578CrossRefPubMedPubMedCentralGoogle Scholar
- Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, Guttridge DC, Grotewold E, Doseff AI (2007) Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation. J Immunol 179:7121–7127CrossRefPubMedGoogle Scholar