Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway

Abstract

Licochalcone A (LicA) is a chalcone extracted from liquorice which has been used as a traditional Chinese medicine for many generations. Increased glucose consumption and glycolytic activity are important hallmarks of cancer cells, and hexokinase 2 (HK2) upregulation is a major contributor to the elevation of glycolysis. Recently, the antitumor activities of LicA have been reported in various cancers; however, its effect on tumor glycolysis in gastric cancer and the underlying mechanisms are completely unknown. In vitro, cell proliferation and clonogenic survival were substantially inhibited after LicA treatment. LicA reduced HK2 expression, and both glucose consumption and lactate production in gastric cancer cells were significantly suppressed. Mechanistic investigations revealed that multiple signaling pathways including Akt, ERK and NF‑κB were suppressed by LicA. Further studies demonstrated that the inhibition of glycolysis by LicA was mainly attributed to the blockade of the Akt signaling pathway, and the suppression of glycolysis was substantially attenuated when Akt was exogenously overexpressed. In addition to the role in the inhibition of glycolysis, reduction in HK2 was confirmed to be involved in the induction of cell apoptosis. The apoptosis induced by LicA was substantially impaired after HK2 overexpression in gastric cancer cells. The in vivo experiment showed that MKN45 xenograft growth was markedly delayed after LicA treatment and HK2 expression in LicA‑treated tissues was markedly decreased. All of these data demonstrated that blockade of the Akt/HK2 pathway was the underlying mechanism required for LicA to exert its biological activities in glycolysis inhibition and apoptosis induction.

Licochalcone A induces apoptotic cell death via JNK/p38 activation in human nasopharyngeal carcinoma cells

“…33 Early reports have indicated that licochalcone A has biological activities, including antiallergic, antiinflammation, antimycobacterial, and anticancer. [6][7][8][9][10]34,35 Our present data provide evidence that licochalcone A can induce apoptotic cell fragmentation, apoptotic body formation, and caspase activation. 36 In particular, casapse-3 has been demonstrated to be a crucial component of the mechanism responsible for the activation of apoptosis in apoptotic cells, and PARP, the cleavage of which is a hallmark of apoptosis, is a well-known downstream target of active caspase-3.…”

“…To overcome these problems, studies on combined therapy have focused on identifying phytotherapeutic agents with known action mechanisms that can augment the therapeutic index of chemotherapeutic agents, such as Lentinan combined with oxaliplatin in hepatocellular carcinoma, baicalein combined with docetaxel in thyroid cancer cells, curcumin combined with platinum in ovarian cancer cells, and Astragalus polysaccharides combined with cisplatin in nasopharyngeal carcinoma cells . Early reports have indicated that licochalcone A has biological activities, including antiallergic, anti‐inflammation, antimycobacterial, and anticancer . Our present data provide evidence that licochalcone A can induce apoptotic cell death in human HONE‐1 nasopharyngeal cancer cells.…”

“…Licochalcone A, a chalconoid, is a phenolic component in the root of Glycyrrhiza glabra and Glycyrrhiza inflate ; it has been shown to have various pharmacologic activities, including antiallergic, anti‐inflammation, antimycobacterial, anti‐legionella, antioxidation, and anticancer . Licochalcone A inhibits lipopolysaccharide‐induced inflammation by targeting NF‐κB activation and the p38/ERK signaling pathway .…”

“…A recent study showed that licochalcone A also suppresses vascular endothelial growth factor‐induced airway smooth muscle cell proliferation by down‐regulating VEGF receptor 2 and caveolin‐1, thereby implying that licochalcone A has the potential for asthma treatment . Recently, licochalcone A has been demonstrated to possess anticancer activities, including inhibition of Akt activity to suppress hexokinase 2‐mediated tumor glycolysis in gastric cancer, down‐regulation of matrix metalloproteinase‐2 expression to inhibit metastasis and induce apoptosis of oral cancer cells, increment of miR‐144‐3p to induce endoplasmic reticulum stress and apoptosis in human lung cancer cells, reduction of PI3K/Akt/mTOR pathway activation to promote autophagy in breast cancer, induction of G2/M arrest, repression of cell invasion via MEK/ERK and ADAM9 signaling pathways in human glioma cells, and induction caspase‐dependent apoptosis in human hepatoma cells . However, the antitumor effect of licochalcone A on human nasopharyngeal carcinoma cells and the underlying mechanisms of such effects remain unknown.…”

“…Licochalcone A, a chalconoid, is a phenolic component in the root of Glycyrrhiza glabra and Glycyrrhiza inflate; it has been shown to have various pharmacologic activities, including antiallergic, antiinflammation, antimycobacterial, anti-legionella, antioxidation, and anticancer. [6][7][8][9][10] Licochalcone A inhibits lipopolysaccharide-induced inflammation by targeting NF-κB activation and the p38/ERK signaling pathway. 7 A recent study showed that licochalcone A also suppresses vascular endothelial growth factor-induced airway smooth muscle cell proliferation by down-regulating VEGF receptor 2 and caveolin-1, thereby implying that licochalcone A has the potential for asthma treatment.…”