HK2 is associated with the Warburg effect and proliferation in liver cancer: Targets for effective therapy with glycyrrhizin.

Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE

Original Publication: Athens, Greece : D. A. Spandidos

Glycyrrhizic Acid/*pharmacology ; Hexokinase/*genetics ; Liver Neoplasms/*drug therapy; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Glycolysis/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/genetics ; Signal Transduction/drug effects ; Warburg Effect, Oncologic/drug effects

Glycyrrhizin (GA) is the most essential active ingredient in licorice root, and has a wide range of biological and pharmacological activities. The present study aimed to conduct a detailed analysis of the effects of GA on liver cancer (LC) cell proliferation and the Warburg effect. Hexokinase‑2 (HK2) is a glycolytic enzyme that catalyzes the Warburg effect. To this end, the LC HepG2 cell line was transfected with small interfering RNA‑HK2 or pCDNA3.1‑HK2, followed by GA treatment. A Cell Counting Kit‑8 assay and EdU staining were employed to evaluate the proliferation rate of LC cells. The expression levels of HK2 and the phosphorylation level of AKT were measured by reverse transcription‑quantitative PCR and western blotting, respectively. Furthermore, the glucose uptake capacity and lactic acid content were assessed by kits, and the glycolysis level was evaluated by assessing the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR). A pronounced increase in the OCR, and decreases in the cell proliferation, glucose uptake capacity, lactic acid content, ECAR and HK2 expression were detected in LC cells subjected to GA treatment or HK2‑knockdown. Conversely, overexpression of HK2 reversed these trends, indicating that glycyrrhizin may inhibit LC cell proliferation and the Warburg effect through suppression of HK2. In addition, it was revealed that the PI3K/AKT signaling pathway was associated with LC cell proliferation and the Warburg effect; notably, treatment of LC cells with the AKT agonist SC79 induced elevation of the ECAR, cell proliferation, glucose uptake capacity, lactic acid content, phosphorylated‑AKT and HK2 expression, and suppressed the OCR. In conclusion, GA may inhibit the Warburg effect and cell proliferation in LC by suppressing HK2 through blockade of the PI3K/AKT signaling pathway.

Erratum in: Mol Med Rep. 2021 Jul;24(1):504. doi: 10.3892/mmr.2021.12143. (PMID: 33982784)

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Keywords: glycyrrhizin; Warburg effect; cell proliferation; PI3K/AKT; hexokinase 2; liver cancer HepG2 cell line

6FO62043WK (Glycyrrhizic Acid)
EC 2.7.1.1 (HK2 protein, human)
EC 2.7.1.1 (Hexokinase)

Date Created: 20210324 Date Completed: 20210510 Latest Revision: 20210706

20250114

PMC7974329

10.3892/mmr.2021.11982

33760124