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Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells.

ABSTRACT: Aberrant regulation of phosphatidylinositol-3-kinases (PI3Ks) is known to be involved in the progression of cancers. PI3K-binding flavonoids such as quercetin and myricetin have been shown to inhibit PI3K activity, but the direct targeting of fisetin to PI3K has not been established. Here, we carried out an in silico investigation of fisetin binding to PI3K and determined fisetin's inhibitory activity in enzymatic and cell-based assays. In addition, fisetin induced apoptosis in human Burkitt's lymphoma Raji cells by inhibiting both PI3Ks and mammalian target of rapamycin (mTOR). Our results indicate that fisetin may serve as a natural backbone for the development of novel dual inhibitors of PI3Ks and mTOR for the treatment of cancer.

SUBMITTER: Lim JY

PROVIDER: S-EPMC5598213 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells.

Lim Ji Yeon JY Lee Joo Yun JY Byun Byung Jin BJ Kim Seong Hwan SH

Toxicology reports 20150713

Aberrant regulation of phosphatidylinositol-3-kinases (PI3Ks) is known to be involved in the progression of cancers. PI3K-binding flavonoids such as quercetin and myricetin have been shown to inhibit PI3K activity, but the direct targeting of fisetin to PI3K has not been established. Here, we carried out an <i>in silico</i> investigation of fisetin binding to PI3K and determined fisetin's inhibitory activity in enzymatic and cell-based assays. In addition, fisetin induced apoptosis in human Burk ...[more]

PMID: 28962438

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Project description:Glycochenodeoxycholate (GCDC) and taurolithocholate (TLC) are hepatotoxic and cholestatic bile salts, whereas tauroursodeoxycholate (TUDC) is cytoprotective and anticholestatic. Yet they all act, in part, through phosphatidylinositol-3-kinase(PI3K)-dependent mechanisms ("PI3K-paradox"). Hepatocytes express three catalytic PI3K Class I isoforms (p110?/?/?), specific functions of which, in liver, are unclear. In other cell types, p110? is associated with detrimental effects. To shed light on the PI3K enigma, we determined whether hydrophobic and hydrophilic bile salts differentially activate distinct p110 isoforms in hepatocytes, and whether p110? mediates bile salt-induced hepatocyte cell death.Isoform-specific PI3K activity assays were established to determine isoform activation by bile salts in rat hepatocytes. Activation of Akt and JNK was determined by immunoblotting. Following stimulation with hydrophobic bile salts, hepatocellular apoptosis was determined morphologically after Hoechst staining and by analysis of caspase-3/-7 activity or caspase-3 cleavage. Activity or expression of PI3K p110? was inhibited pharmacologically (AS604850) or by knock-down using specific siRNA.All bile salts tested activated p110?, while p110? was activated by TUDC and GCDC. Intriguingly, only hydrophobic bile salts activated p110?. Inhibition of p110? attenuated GCDC-induced Akt- and JNK-activation, but did not alter TUDC- or cAMP-induced Akt-signaling in rat hepatocytes. Inhibition or knock-down of p110? markedly attenuated hydrophobic bile salt-induced apoptosis in rat hepatocytes and human hepatoma cell lines but did not alter Fas-, tumor necrosis factor ?- and etoposide-induced apoptosis. Depletion of Ca(++) prevented GCDC-induced toxicity in rat hepatocytes but did not affect GCDC-induced Akt- and JNK-activation.PI3K p110? is activated by hydrophobic, but not hydrophilic bile salts. Bile salt-induced hepatocyte apoptosis is partly mediated via a PI3K p110? dependent signaling pathway, potentially involving JNK.

Dataset Information

Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells.

Publications

Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells.

Similar Datasets

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