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Int. J. Mol. Sci. 2015, 16(4), 8415-8429; doi:10.3390/ijms16048415

Autophagy Induction by Silibinin Positively Contributes to Its Anti-Metastatic Capacity via AMPK/mTOR Pathway in Renal Cell Carcinoma

1
Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
2
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710061, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Sanjay K. Srivastava
Received: 13 February 2015 / Revised: 24 March 2015 / Accepted: 3 April 2015 / Published: 15 April 2015
(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)
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Abstract

Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC. View Full-Text
Keywords: renal cell carcinoma; silibinin; autophagy; AMPK; migration; invasion renal cell carcinoma; silibinin; autophagy; AMPK; migration; invasion
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Li, F.; Ma, Z.; Guan, Z.; Chen, Y.; Wu, K.; Guo, P.; Wang, X.; He, D.; Zeng, J. Autophagy Induction by Silibinin Positively Contributes to Its Anti-Metastatic Capacity via AMPK/mTOR Pathway in Renal Cell Carcinoma. Int. J. Mol. Sci. 2015, 16, 8415-8429.

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