Cucurbitacin-I induces hypertrophy in H9c2 cardiomyoblasts through activation of autophagy via MEK/ERK1/2 signaling pathway.
Cucurbitacin-I, a natural triterpenoids initially identified in medicinal plants, shows a potent anticancer effect on a variety of cancer cell types. Nevertheless, the cardiotoxicity of cucurbitacin-I has not heretofore been reported. In this study, the mechanisms of cucurbitacin-I-induced cardiotoxicity were examined by investigating the role of MAPK-autophagy-dependent pathways. After being treated with 0.1-0.3μM cucurbitacin-I for 48h, H9c2 cells showed a gradual decrease in the cell viabilities, a gradual increase in cell size, and mRNA expression of ANP and BNP (cardiac hypertrophic markers). Cucurbitacin-I concentration-dependent apoptosis of H9c2 cells was also observed. The increased apoptosis of H9c2 cells was paralleling with the gradually strong autophagy levels. Furthermore, an autophagy inhibitor, 3-MA, was used to block the cucurbitacin-I-stirred autophagy, and then the hypertrophy and apoptosis induced by 0.3μM cucurbitacin-I were significantly attenuated. In addition, cucurbitacin-I exposure also activated the MAPK signaling pathways, including ERK1/2, JNK, and p38 kinases. Interestingly, only the ERK inhibitor U0126, but not the JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580, weakened the induction of 0.3μM cucurbitacin-I in hypertrophy, autophagy and apoptosis. Our findings suggest that cucurbitacin-I can increase the autophagy levels of H9c2 cells, most likely, through the activation of an ERK-autophagy dependent pathway, which results in the hypertrophy and apoptosis of cardiomyocytes.
School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Yao
Y
Wu
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Hongying
H
Chen
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Ruli
R
Li
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Xiaoxiao
X
Wang
School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China.
He
H
Li
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Juanjuan
J
Xin
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Zhiqiang
Z
Liu
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Sisi
S
Wu
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China. Electronic address: wcumsjw@scu.edu.cn.
Wei
W
Jiang
School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China. Electronic address: zhuling529@163.com.
Ling
L
Zhu
D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced* / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D032386:Myoblasts, Cardiac / Q000187:drug effects*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014315:Triterpenes; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; C093642:SB 203580; C038106:cucurbitacin I
Autophagy; Cardiomyocyte hypertrophy; Cucurbitacin-I; MEK/ERK1/2; U0126