Glycyrrhetinic Acid triggers a protective autophagy by activation of extracellular regulated protein kinases in hepatocellular carcinoma cells.
Glycyrrhetinic acid (GA), one of the main constituents of the famous Chinese medicinal herb and food additive licorice (Glycyrrhiza uralensis Fisch), has been indicated to possess potential anticancer effects and is widely utilized in hepatocellular carcinoma (HCC) targeted drug delivery systems (TDDS) due to the highly expressed target binding sites of GA on HCC cells. This study found that GA reduced the cell viability, increased the release of lactate dehydrogenase, and enhanced the expression of Bax, cleaved caspase-3, and LC3-II in HCC cells. The GA-triggered autophagy has been further confirmed by monodansylcadaverine staining as well as transmission electron microscopy analysis. The cell viability was obviously decreased whereas the expression of cleaved caspases was significantly increased when inhibition of autophagy by choloroquine or bafilomycin A1, suggesting that GA triggered a protective autophagy. Extracellular regulated protein kinase (ERK) was activated after treatment with GA in HepG2 cells and pretreatment with U0126 or PD98059, the MEK inhibitors, reversed GA-triggered autophagy as evidenced by decreased expression of LC3-II and formation of autophagosomes, respectively. Furthermore, GA-induced cell death and apoptosis were enhanced after pretreatment with PD98059. This is the first report that GA triggers a protective autophagy in HCC cells via activation of ERK, which might attenuate the anticancer effects of GA or chemotherapeutic drugs loaded with GA-modified TDDS.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao, China.
Zheng-Hai
ZH
Tang
Ting
T
Li
Lin-Lin
LL
Chang
Hong
H
Zhu
Yun-Guang
YG
Tong
Xiu-Ping
XP
Chen
Yi-Tao
YT
Wang
Jin-Jian
JJ
Lu
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D029882:Glycyrrhiza uralensis / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020011:Protective Agents / Q000494:pharmacology*
D004365:Drugs, Chinese Herbal; D020011:Protective Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D006034:Glycyrrhetinic Acid
ERK; autophagy; glycyrrhetinic acid; hepatocellular carcinoma; protective