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Food-derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites

ABSTRACT: Cancer cells often exhibit extreme sensitivity to splicing inhibitors. We identified food-derived flavonoids, apigenin and luteolin, as compounds that modulate mRNA splicing at the genome-wide level, followed by proliferation inhibition. They bind to mRNA splicing-related proteins to induce a widespread change of splicing patterns in treated cells. Their inhibitory activity on splicing is relatively moderate, and introns with weak splice sites tend to be sensitive to them. Such introns remain unspliced, and the resulting intron-containing mRNAs are retained in the nucleus, resulting in the nuclear accumulation of poly(A)+ RNAs in these flavonoid-treated cells. Tumorigenic cells are more susceptible to these flavonoids than non-tumorigenic cells, both for the nuclear poly(A)+ RNA-accumulating phenotype and cell viability. This study illustrates the possible mechanism of these flavonoids to suppress tumor progression in vivo that were demonstrated by previous studies, and provides the potential of daily intake of moderate splicing inhibitors to prevent cancer development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128097 | GEO | 2019/11/25

REPOSITORIES: GEO

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Project description:Age is the primary risk factor for many chronic diseases and cognitive decline during brain aging may increase dementia risk. Hallmarks of brain aging including neuronal dysfunction and glial contribute to reduced cognitive function, and there is a persistent lack of effective treatments. Bioactive plant compounds called “nutraceuticals” can target age-related cellular processes and may protect cognitive function. Apigenin is a flavone found in plants such as chamomile and can inhibit hallmarks of aging such as cellular senescence, mitochondrial dysfunction, and impaired proteostasis. However, the underlying mechanisms of apigenin in the brain are not fully understood. Here, we characterized brain transcriptome changes in young and old mice given apigenin in drinking water and examined potential mechanisms in human astrocytes. Consistent with previous studies, we observed improved novel object recognition in old mice treated with apigenin versus old controls. Transcriptome analyses in old controls found differentially expressed genes related to immune responses, inflammation, and cytokine regulation versus young. Fewer differences were observed in old apigenin-treated versus old controls, but these changes were related to development, behavior, and antiviral responses. The majority of upregulated genes in old mice were downregulated with apigenin treatment and associated with immune responses. Similarly, the genes that were reduced with aging, but increased in old apigenin-treated mice were related to pathways important for neurological function/disease, cellular maintenance, and homeostatic signaling. We also found that glial cells drove the majority of the transcriptome differences with aging and apigenin-treatment. To explore the mechanism of action for apigenin in glial cells, we treated replicatively aged astrocytes with apigenin and observed reduced markers of inflammation and cellular senescence. Collectively, our data support the role of apigenin as a protector of cognitive and neuronal function protectant through the suppression of neuroinflammatory genes and proteins and may be especially important in non-neuronal cells.

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Food-derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites

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