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Molecules 2017, 22(11), 1934; doi:10.3390/molecules22111934

Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells

1
School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
2
State Key Laboratory of Biotherapy, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
3
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 19 October 2017 / Revised: 7 November 2017 / Accepted: 7 November 2017 / Published: 11 November 2017
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Abstract

Liver cancer is a progressive, irreversible and aggressive malignant disease, which has no effective chemotherapeutic drugs. RA-XII, a natural cyclopeptide isolated from the traditional Chinese medicine Rubia yunnanensis, exerts anti-cancer and anti-inflammatory activities. This work aimed to investigate the effects of RA-XII on a hepatic tumor and its underlying mechanisms in human hepatoma HepG2 cells. The results showed that RA-XII effectively inhibited the proliferation of HepG2 cells. Consistently, RA-XII significantly induced apoptosis in HepG2 cells by decreasing the expression of caspase 3, 8, 9, and promoting the Cleavage of PARP. Moreover, RA-XII-induced apoptosis was attenuated in the presence of apoptosis inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl keton, suggesting that RA-XII induced apoptosis-cell-death in HepG2 cells. Furthermore, autophagy-related proteins and mRNA levels were dramatically reduced after RA-XII treatment. Meanwhile, we observed that autophagy inhibitor chloroquine could enhance apoptosis in RA-XII-treated HepG2 cells, indicating that autophagy played a protective role in HepG2 cells and RA-XII might inhibit protective autophagy. Further analysis showed that RA-XII inhibited AMPK phosphorylation and led to the mTOR/P70S6K pathway activation, suggesting that RA-XII inhibited autophagy through AMPK/mTOR/P70S6K pathways. This study demonstrated that RA-XII promoted apoptosis and inhibited protective autophagy through AMPK/mTOR/P70S6K pathways in HepG2 cells. In conclusion, these findings suggest that RA-XII might potentially be a candidate as an autophagy inhibitor agent for further therapy of liver cancer. View Full-Text
Keywords: RA-XII; cyclopeptide; autophagy; apoptosis; mTOR; HepG2 liver cancer cells RA-XII; cyclopeptide; autophagy; apoptosis; mTOR; HepG2 liver cancer cells
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MDPI and ACS Style

Song, L.; Wang, Z.; Wang, Y.; Guo, D.; Yang, J.; Chen, L.; Tan, N. Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells. Molecules 2017, 22, 1934.

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