Abstract
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4′,5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.
Highlights
Warburg effect refers to the energy metabolism of cancer cells that depends on anaerobic glycolysis for completion
Enhanced glucose consumption and lactate excretion promote the Warburg effect, which is associated with oncogenic growth [9]. e Warburg effect is one of the hallmarks of cancer cells and is characterized by enhanced aerobic glycolysis, and the Warburg effect provides a theory of an inhibitory role in tumorigenesis [10]
SOSP-9607 and U-2OS cells were cultured in RPMI-1640 medium (Hyclone, UT, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, Gaithersburg, MD, USA)
Summary
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents [1] and accounts for approximately 5% of all cases of childhood cancer [2]. Despite many efforts, such as surgical resection combined with radiotherapy and/or chemotherapy, the fiveyear survival rate of patients with OS is only 60% because of the high recurrence rate, metastasis, and poor prognosis [3–5]. Valproic acid reduces glucose uptake and decreases lactate and ATP production to inhibit aerobic glycolysis in neuroblastoma cells, inhibiting the Warburg effect and tumor progression [8]. Galangin reverses the Warburg effect in hepatocellular carcinoma cells, inhibits hepatocellular
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