Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase

Abstract

Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-α-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-α on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-α-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-α-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-α on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/β.

Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke‐induced airway inflammation

“…Furthermore, medicinal plants and foods are also the main resource of bioactive compounds, including flavonoids. Recently, several flavonoids have been proved to be useful for the treatment of various diseases, such as cancer (Igbe et al, ), cardiovascular diseases (Xu et al, ), and infectious diseases (Shen et al, ). The total flavonoids from sea buckthorn has been long used for the treatment of cardiovascular diseases (Xu et al, ).…”

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

“…Quercetin antitumor effects have been described in different cancer types, including HCC [1]. In 25 of the articles included in the present review, quercetin efficacy as single treatment was evaluated employing different HCC study models [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]46,48,49,[51][52][53][54]57]. Antiproliferative effect of this flavonoid alone has been demonstrated in several researches with in vitro models [22][23][24][25][26][27][30][31][32][33]35,38,46,48,49,[51][52][53][54], highlighting the HepG2 cell line as the most used in 21 of the 25 articles [24,25,<...>…”

“…Furthermore, it has been described that quercetin-derived inhibition of liver cancer cell growth could be mediated by the disruption of different pathways, including protein kinase B (Akt)/mammalian target of rapamycin (mTOR) [23,24], mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2) [27,38] and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling routes [22]. Induction of p53 as consequence of phosphatidyl inositol 3 kinase (PI3K) and protein kinase C (PKC) downregulation was also linked to antiproliferative effects in liver tumor cells [31], in addition to the blockade of Src homology domain 2 containing tyrosine phosphatase-1/2 (SHP-1/2) activity through directly interacting with quercetin [48]. A group of researchers also observed that this flavonoid was able to abrogate the transcription factor specificity protein 1 (Sp1) expression leading to suppression of HepG2 cell proliferation [33], thus increasing the number of cellular pathways that may be altered by quercetin.…”

Quercetin‐mediated regulation of signal transduction cascades and microRNAs: Natural weapon against cancer

“…Quercetin worked synergistically with bortezomib against primary effusion lymphoma cells. 12 As shown in Figure 1A, SHP2 negatively regulated the JAK/STAT pathway mainly through dephosphorylation of activated JAKs and STATs. 10 Quercetin has also previously been reported to work effectively with epigallocatechin-3-gallate (EGCG) against cholangiocarcinoma (CCA) cells.…”

“…9 Combinatorial treatment of diffuse large B-cell lymphoma with quercetin and rituximab resulted in marked suppression of STAT3 pathway. 12 It was suggested that quercetin potentiated antiproliferative effects exerted by interferon-α in HCC cells via the activation of JAK-STAT pathway. 11 Both natural products dose-dependently reduced phosphorylated levels of STAT1 and STAT3.…”