In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity

Abstract

Glycolysis, as an altered cancer cell-intrinsic metabolism, is an essential hallmark of cancer. Phosphofructokinase (PFK) is a metabolic sensor in the glycolytic pathway, and restricting the substrate availability for this enzyme has been researched extensively as a target for chemotherapy. In the present study, we investigated that the effects of epigallocatechin-3-gallate (EGCG), an active component of green tea, on inhibiting cell growth and inducing apoptosis by promoting a metabolic shift away from glycolysis in aerobic glycolytic hepatocellular carcinoma (HCC) cells. EGCG modulated the oligomeric structure of PFK, potentially leading to metabolic stress associated apoptosis and suggesting that EGCG acts by directly suppressing PFK activity. A PFK activity inhibitor enhanced the effect, while the allosteric activator reversed EGCG-induced HCC cell death. PFK siRNA knockdown-induced apoptosis was not reversed by the activator. EGCG enhanced the effect of sorafenib on cell growth inhibition in both aerobic glycolytic HCC cells and in a xenograft mouse model. The present study suggests a potential role for EGCG as an adjuvant in cancer therapy, which merits further investigation at the clinical level.

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

“…a ). Among them, HCC‐LM3 displayed the highest IC 50 for sorafenib, and was regarded as a typical innate sorafenib‐resistant HCC cell line, which was consistent with the conclusions of previous reports . The IC 50 of the acquired sorafenib‐resistant Huh7‐R cells was 26.10 ± 1.73 μM, much higher than for sorafenib‐naïve Huh7 cells ( p < 0.001).…”

“…Among them, HCC-LM3 displayed the highest IC 50 for sorafenib, and was regarded as a typical innate sorafenib-resistant HCC cell line, which was consistent with the conclusions of previous reports. 29,30 The IC 50 of the acquired sorafenib-resistant Huh7-R cells was 26.10 6 1.73 lM, much higher than for sorafenib-na€ ıve Huh7 cells (p < 0.001). The prominent sorafenib resistance of HCC-LM3 and Huh7-R cells was also confirmed by flow cytometry compared with Huh7 cells when treated with 10 lM sorafenib (apoptosis rate of Huh7-R vs. Huh7: 1.…”

Therapeutic potential of PPARγ natural agonists in liver diseases

“…The protective effects of many Chinese herbal medicines, such as quercetin, [51][52][53] oleanolic acid, 54 proanthocyanidin B2, 55 epigallocatechin-3-gallate, 56 isorhamnetin 57 and genistein, 58 in liver diseases have been confirmed by our studies.…”

Phytotherapeutics in cancer invasion and metastasis

“…Epigallocatechin‐3‐gallate (ECGC; Figure ), the main component found in green tea, was evaluated in hepatocellular carcinoma both in vitro and in vivo. EGCG plus sorafenib inhibited cell growth both in cell lines and xenografted mice, specifically targeting the glycolytic pathway (Li et al, ).…”