Ginkgol C17:1 inhibits tumor growth by blunting the EGF- PI3K/Akt signaling pathway

Abstract

Ginkgol C17:1 has been shown to inhibit apoptosis and migration of cancer cells, but the underlying mechanisms are not fully elucidated. In this study, we explored whether the inhibitory effects of Ginkgol C17:1 were associated with epidermal growth factor receptor (EGFR) and PI3K/Akt signaling. The results showed that EGF treatment increased the phosphorylation of EGFR, PI3K, Akt, mTOR and NF-kB, and also enhanced the proliferation, migration and invasion of HepG2 cells. Ginkgol C17:1 dose-dependently inhibited EGF-induced phosphorylation/activation of all the key components including EGFR, PI3K, Akt, mTOR and NF-kB, leading to a significant reduction either of proliferation or migration and invasion of HepG2 cells. Notably, treatment with Ginkgol C17:1 in mice suppressed the growth of tumor massin vivo, and expression of EGFR in the tumor tissue. The results suggest that Ginkgol C17:1 is a potent tumor inhibiting compound that acts on EGF-induced signal transduction of the PI3K/Akt signaling pathways, and may represent a clinically interesting candidate for cancer therapy.

Keywords

Ginkgol C17:1 / epidermal growth factor / PI3K/Akt / HepG2

References

[1] Prigent SA, Lemoine  NR. The type 1 (EGFR-related) family of growth factor receptors and their ligands[J]. Prog Growth Factor Res, 1992, 4(1): 1–24

[2] Normanno N, Bianco  C, De Luca A , Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment[J]. Endocr Relat Cancer, 2003, 10(1): 1–21

[3] Hynes NE, MacDonald  G. ErbB receptors and signaling pathways in cancer[J]. Curr Opin Cell Biol, 2009, 21(2): 177–184

[4] Sharma SV, Bell  DW, Settleman J , Epidermal growth factor receptor mutations in lung cancer[J]. Nat Rev Cancer, 2007, 7(3): 169–181

[5] Boonsai P, Phuwapraisirisan  P, Chanchao C . Antibacterial activity of a cardanol from Thai Apis mellifera propolis[J]. Int J Med Sci, 2014, 11(4): 327–336

[6] Meng ZL, Wei  Y, Xu DM , Effect of 2-allylphenol against Botrytis cinerea Pers., and its residue in tomato fruit[J]. Crop Prot, 2007, 26: 1711–1715.

[7] Shi QT, Liu  H, Zhang YZ , Study on antifeeding activity of ginkgo phenol to cannage caterpillar[J]. Biomass Chem Engineer, 2009, 43(1): 13–16.

[8] Trevisan MT, Pfundstein  B, Haubner R , Characterization of alkyl phenols in cashew (Anacardium occidentale) products and assay of their antioxidant capacity[J]. Food Chem Toxicol, 2006, 44(2): 188–197

[9] Zhou C, Li  X, Du W , Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis[J]. Chemotherapy, 2010, 56(5): 393–402

[10] Sukumari-Ramesh S, Singh  N, Jensen MA , Anacardic acid induces caspase-independent apoptosis and radiosensitizes pituitary adenoma cells[J]. J Neurosurg, 2011, 114(6): 1681–1690

[11] Tan WH, Shen  ZB, Wang CZ , Isolation and identification of alkylphenols from Ginkgo biloba leaves[J]. Chem. Ind. Forest Prod, 2001, 21(4): 1–6.

[12] Fang YY, Yang  XM, Li YY , Spectroscopic studies on the interaction of bovine serum albumin with Ginkgol C15:1 from Ginkgo biloba L[J]. Luminesceence, 2015, 162: 203–211.

[13] Yang XM, Wang  YF, Li YY , Thermal stability of ginkgolic acids from Ginkgo biloba and the effects of ginkgol C17:1 on the apoptosis and migration of SMMC7721 cells[J]. Fitoterapia, 2014, 98: 66–76

[14] Wang YF, Yang  XM, Li YY , Inhibitory effect of ginkgols on SMMC-7721 liver cancer cells in vitro and liver cancer H22-braring mice in vivo[J]. J Jiangsu Univ (Med Edit) (in China), 2013, 23(3):233–237.

[15] Osaki M, Oshimura  M, Ito H . PI3K-Akt pathway: its functions and alterations in human cancer[J]. Apoptosis, 2004, 9(6): 667–676

[16] Sun DX, Cai  ZY. EGFR/PI3K/Akt signaling pathway with tumor[J]. Lab Med, 2014, 29(7): 768–773.

[17] Song G, Ouyang  G, Bao S . The activation of Akt/PKB signaling pathway and cell survival[J]. J Cell Mol Med, 2005, 9(1): 59–71

[18] Edwards LA, Thiessen  B, Dragowska WH , Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth[J]. Oncogene, 2005, 24(22): 3596–3605

[19] Berg M, Soreide  K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy[J]. Discov Med, 2012, 14(76): 207–214

[20] Marone R, Cmiljanovic  V, Giese B , Targeting phosphoinositide 3-kinase: moving towards therapy[J]. Biochim Biophys Acta, 2008, 1784(1): 159–185

Acknowledgments

This study was supported by the National Natural Science Foundation of China (grant no. 81372404), and the Postdoctoral Foundation of China (grant no. 2012M521018) to Yueying Li; the Zhenjiang Social Development Project (No. SH2015072) to Yaxiang Shi.

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