Dietary intake of genistein suppresses hepatocellular carcinoma through AMPK-mediated apoptosis and anti-inflammation

Abstract

BackgroundWomen have a lower risk of hepatocellular carcinoma (HCC) than men, and the decreased possibility of HCC in women is thought to depend on estrogen levels. As a soybean-isoflavone product, genistein has estrogenic activity in various reproductive tissues, because it mimics 17β-estradiol and binds the estrogen receptor. Though genistein is a known liver cancer suppressor, its effects have not been studies in long-term experiment, where genistein is fed to a female animal model of HCC.MethodsMice were treated with diethylnitrosamine (DEN) to induce HCC at 2 weeks of age and fed with supplemental genistein for 5 months, from 40 to 62 weeks of age.ResultsThe dietary intake of genistein decreased the incidence of HCC and suppressed HCC development. Genistein induced phospho-AMPK in total liver extracts, Hep3B cells, and Raw 264.7 cells, and phospho-AMPK promoted apoptosis in liver and Hep3B cells. Moreover, phospho-AMPK down-regulated pro-inflammatory responses and ameliorated liver damage. A suppressed pro-inflammatory response with increased mitochondrial respiration was concomitantly observed after genistein treatment.ConclusionsGenistein-mediated AMPK activation increases hepatocyte apoptosis through energy-dependent caspase pathways, suppresses the inflammatory response in resident liver macrophages by increased cellular respiration, and consequently inhibits the initiation and progression of HCC.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5222-8) contains supplementary material, which is available to authorized users.

The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma

“…Hence, the significant AMPK determinants activity are conformational switch induced by AMP and the α subunit phosphorylation on Thr172 (Figure 1). A series of reviews have reported the downstream signal pathways involving AMPK activity such as mitochondrial biogenesis, autophagy and inflammation response, as well summarized in other reviews [25,31,32]. Some downstream signal pathways of AMPK are shown in Figure 1.…”

Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances

“…It has also been postulated that genistein enhanced the phosphorylation and activation of p53, while decreased the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt (also known as protein kinase B), which result in cells undergoing apoptosis (Ouyang et al, 2009). Genistein-mediated activated protein kinase (AMPK) upregulation increased apoptosis of hepatocytes, in hepatocellular carcinoma (HCC) through energy-dependent caspase pathway (Lee et al, 2019). In Hep3B cells, genistein activated AMPK, which promoted apoptosis accompanied by downregulation of the proinflammatory responses and increasing mitochondrial respiration.…”

Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

“…29 Suppression of the pro-inflammatory response by KCs could inhibit the initiation of HCC but could promote the progression of HCC. 30 As determined by Lee et al, 30 in accordance with enhanced inflammation, there were significant increases in hepatic inflammation, fibrosis and tumor growth in mice fed a high-fat diet, which might be attributed to the pro-inflammatory, profibrogenic and pro-tumoral responses mediated by vascular endothelial growth factor-dependent angiogenesis of KCs. 31 It is therefore inferred that liver macrophage phenotypes are not fixed and that their dynamic alterations are implicated in hepatocarcinogenesis and its progression.…”