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. 2022 Mar 9:2022:3983637.
doi: 10.1155/2022/3983637. eCollection 2022.

Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

Yihua Shi  1 , Kai Lian  1 , Jiguang Jia  1
Affiliations

Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

Yihua Shi et al. Evid Based Complement Alternat Med. .

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.

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Conflict of interest statement

All authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The effect of apigenin on the viability of SOSP-9607, U-2OS, and MG-63 cells was evaluated by the CCK-8 assay. Data represent the mean ± standard deviation (n = 3).
Figure 2
Figure 2
Apigenin attenuates the proliferation and epithelial-mesenchymal transition (EMT) of SOSP-9607 cells. (a) SOSP-9607 cell proliferation was assessed using the clone formation assay. (b) Migration and invasion of SOSP-9607 cells were examined using the transwell assay. (c) Expression of EMT-related proteins (vimentin and E-cadherin) was measured by western blot. Data represent the mean ± standard deviation. (n = 3). ∗∗∗P < 0.001.
Figure 3
Figure 3
Apigenin attenuates the stem-like properties of SOSP-9607 cells. (a) Tumorsphere formation of SOSP-9607 cells. (b) The proportion of SOSP-9607 cells with positive expression of Nanog and OCT-4 was detected by flow cytometry. Data represent the mean ± standard deviation (n = 3). ∗P < 0.05, ∗∗∗P < 0.001.
Figure 4
Figure 4
Apigenin suppresses the Warburg effect in SOSP-9607 cells. (a) Levels of glucose, lactic acid, citrate, and APT were measured using corresponding kits. (b) Expression of metabolism-related enzymes associated with the Warburg effect (GLUT1, HK1, and LDHA) was detected by western blot. Data represent the mean ± standard deviation. (n = 3). ∗P < 0.05, ∗∗∗P < 0.001.
Figure 5
Figure 5
Apigenin inhibits the activation of PI3K/Akt/mTOR signaling in SOSP-9607 cells. The expression and phosphorylation of PI3K, Akt, and mTOR were evaluated by western blot. Data represent the mean ± standard deviation (n = 3). ∗P < 0.05, ∗∗∗P < 0.001.
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