Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids

Abstract

In this study, we have investigated the underlying molecular mechanism for the potent proapoptotic effect of luteolin on human hepatoma cells both in vitro and in vivo, focusing on the signal transducer and activator of transcription 3 (STAT3)/Fas signaling. A clear apoptosis was found in the luteolin-treated HLF hepatoma cells in a time-and dosagedependent manner. In concert with the caspase-8 activation by luteolin, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr 705 phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was found within 20 minutes in the luteolin-treated cells, leading to down-regulation in the target gene products of STAT3, such as cyclin D1, survivin, Bcl-xL, and vascular endothelial growth factor. Of interest, the rapid downregulation in STAT3 was consistent with an accelerated ubiquitin-dependent degradation in the Tyr 705 -phosphorylated STAT3, but not the Ser 727 -phosphorylated one, another regulator of STAT3 activity. The expression level of Ser 727 -phosphorylated STAT3 was gradually decreased by the luteolin treatment, followed by a fast and clear down-regulation in the active forms of CDK5, which can phosphorylate STAT3 at Ser 727 . An overexpression in STAT3 led to resistance to luteolin, suggesting that STAT3 was a critical target of luteolin. In nude mice with xenografted tumors using HAK-1B hepatoma cells, luteolin significantly inhibited the growth of the tumors in a dosage-dependent manner. These data suggested that luteolin targeted STAT3 through dual pathways-the ubiquitin-dependent degradation in Tyr 705 -phosphorylated STAT3 and the gradual down-regulation in Ser 727 -phosphorylated STAT3 through inactivation of CDK5, thereby triggering apoptosis via up-regulation in Fas/CD95.

Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

“…In the present study, it was found that the JAK/STAT3 cascade of CCA cells was suppressed by luteolin. Indeed, luteolin has been shown to promote the degradation of STAT3 in human hepatoma cells (Selvendiran et al, 2006). Additionally, luteolin has been shown to exert its effects through inhibition of several signaling pathways such as AMPK and NF-κB as demonstrated in hepatocarcinoma cells (Hwang et al, 2011).…”

Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin

“…Numerous studies have shown the antiproliferation activity and possible mechanisms of luteolin in many types of human cancers. Luteolin was found to inhibit epidermal growth factor receptor tyrosine kinase activity (29), to promote degradation of signal transducer and activator of transcription 3 (15), to up-regulate expression of death receptor 5 (30), to inactivate IGF-I/IGF-IR singling (24), and to inhibit expression of androgen receptor (31). However, the effect of luteolin on invasion of cancer cells remains unknown.…”

“…Luteolin was found to inhibit proliferation (12)(13)(14) and induce apoptosis of cancer cells (13,15). It may function to sensitize tumor necrosis factor α-and cisplatin-induced apoptosis of human tumor cells (16)(17)(18).…”

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

“…Similarly, treatment of human colon carcinoma HT-29 cells with dietary flavone led to post-G1 arrest and apoptosis, preceded by changes in membrane permeability, DNA fragmentation and increased expression of p21, Bak and decreased expression of cyclin B, cyclin E and Bcl-x L [5]. Additionally, luteolin, present in capsicum pepper, caused an increase in the apoptotic hepatoma cell death, which was consistent with a caspase-8 activation, enhanced expression of Fas/CD45 and decreased signal transducers and activators of transcription (STAT)3, survivin and Bclx L expression levels [111], whereas this flavonoid triggered the mitochondrial pathway of apoptosis in different hepatoma cells as shown by the activation of caspases-3 and -9, release of cytochrome c and increased translocation of Bax/ Bak to the mitochondria [112].…”