Anti-neoplastic Effect of Ginkgolide C through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma Cells.

Min Hee Yang,Kwang Seok Ahn,Jae-Young Um,Seung Ho Baek

doi:10.3390/ijms21218303

Min Hee Yang, Kwang Seok Ahn + Show 2 more

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https://doi.org/10.3390/ijms21218303

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Abstract

Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC.

Highlights

Hepatocellular carcinoma (HCC) is a lethal malignancy and third leading cause of mortality among cancer patients in the world [1,2,3,4]
We analyzed if Ginkgolide C (GGC) could affect c-mesenchymal–epithelial transition receptor (c-Met) activation in hepatocellular carcinoma cells
We investigated if GGC can modulate the phosphorylation of c-Met and downstream signaling cascades

Summary

Introduction

Hepatocellular carcinoma (HCC) is a lethal malignancy and third leading cause of mortality among cancer patients in the world [1,2,3,4]. Early-stage HCC patients can be treated with liver resection. C-Met is a receptor tyrosine kinase (RTK) that can be activated by hepatocyte growth factor (HGF) [14]. The stimulation of c-Met activity leads to the rapid phosphorylation of downstream signals, such as RAS, MAPK, PI3K, and Akt, that can regulate cell growth, metastasis, survival, and motility [15,16,17,18,19,20]. HGF/c-Met elevation have been associated with metastatic progression in many major human cancers [22,23]. Gao et al found that a common polyphenol, resveratrol, can attenuate HCC growth through targeting the HGF-c-Met signaling pathway, thereby further implicating the possibility that c-Met can be used as a suitable molecular target for prevention and clinical treatment of HCC [10]

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