Quercetin Inhibits the Proliferation of Glycolysis-Addicted HCC Cells by Reducing Hexokinase 2 and Akt-mTOR Pathway

Abstract

Increased glycolysis in tumor cells is associated with increased risk of tumor progression and mortality. Therefore, disruption of glycolysis, one of the main sources of cellular energy supply, can serve as a target for suppressing tumor growth and progression. Of note, hexokinase-2 (HK2) plays vital roles in glucose metabolism. Moreover, the expression of HK2 alters the metabolic phenotype and supports the continuous growth of tumor cells, making it an attractive target for cancer therapy. Quercetin (QUE), a bioactive flavonoid, has a profound anti-tumor effect on hepatocellular carcinoma (HCC), but the precise underlying mechanism of this effect is unclear. In the present study, we reported that QUE inhibited the proliferation of HCC cells that relied on aerobic glycolysis. We further found that QUE could decrease the protein levels of HK2 and suppress the AKT/mTOR pathway in HCC cells. In addition, QUE significantly restrained the growth of HCC xenografts and decreased HK-2 expression in vivo. Taken together, we have revealed that QUE suppresses the progression of HCC by inhibiting HK2-dependentglycolysis, which may have a promising potential to be an effective treatments for HCC, especially for those patients with high HK2 expression.

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

“…Cell growth inhibition, in addition to apoptosis stimulation, were the main processes described as quercetin mechanisms of action against HCC, properties that have also been observed in different tumors, such as non-small cell lung cancer [64] and breast cancer [65,66]. Although almost studies associated antiproliferative activity of quercetin with alteration of several pathways, Akt/mTOR and MEK1/ERK1/2 signaling routes were mostly found to be regulated by this flavonoid, either as free drug as well as encapsulated [23,24,27,38,42]. NF-κB-dependent pathway suppression after quercetin-loaded nanoparticles or quercetin combination therapy was also observed by two groups [42,47], however this route has not been analyzed in HCC cells treated with quercetin alone, despite the well-known role of signaling routes such as JAK/STAT and NF-κB pathways in liver cancer development [67].…”

“…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,<...>…”

“…This ability to reverse glycolytic metabolism of liver cancer cells is often related to the efficacy of antitumor drugs such as quercetin [61]. 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].…”

“…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 [24,25,27,28,[30][31][32][33][35][36][37][38]46,[48][49][50][51][52][53][54]57]. After administration of quercetin, changes in tumor cell morphology in HepG2, HuH7, PLC/PRF-5, Hep3B and LM3 lines [22,25,30,31] as well as suppression of glycolytic metabolism in SMMC-7721 and BEL-7402 HCC cell lines [23] were associated with antitumor properties in HCC. This ability to reverse glycolytic metabolism of liver cancer cells is often related to the efficacy of antitumor drugs such as quercetin…”

“…By last, despite the numerous studies conducted with quercetin, only three publications have included animal models to complete in vitro results [22][23][24]. Growth inhibitory activity of this flavonoid was demonstrated in all of them [22][23][24], describing a proapoptotic effect mediated, at least in part, by autophagy induction against LM3 and SMMC7721 HCC lines [22,24].…”