Etoposide Induces Apoptosis in Activated Human Hepatic Stellate Cells via ER Stress.
The activation of hepatic stellate cells (HSCs) plays a vital role in the progression of liver fibrosis, and the induction of HSCs apoptosis may attenuate or reverse fibrogenesis. The therapeutic effects of etoposide(VP-16), a widely used anticancer agent, on HSCs apoptosis and liver fibrosis resolution are still unclear. Here, we report that VP-16 reduced the proliferation of LX-2 cells and led to significantly high levels of apoptosis, as indicated by Annexin V staining and the proteolytic cleavage of the executioner caspase-3 and PARP. Additionally, the unfolded protein response regulators CHOP, BIP, caspase-12, p-eIF2α and IRE1α, which are considered endoplasmic reticulum (ER) stress markers, were upregulated by VP-16. The strong inhibitory effect of VP-16 on LX-2 cells was mainly dependent on ER stress, which activated JNK signaling pathway. Remarkably, VP-16 treatment decreased the expression of α-SMA and type I collagen and simultaneously increased the ratio of matrix metalloproteinases (MMPs) to tissue inhibitor of matrix metalloproteinases (TIMPs). In contrast, VP-16 induced significantly more apoptosis in HSCs than in normal hepatocytes. Taken together, our findings demonstrate that VP-16 exerts a proapoptotic effect on LX-2 cells and has an antifibrogenic effect on collagen deposition, suggesting a new strategy for the treatment of liver fibrosis.
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Chen
C
Wang
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Feng
F
Zhang
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Yu
Y
Cao
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Mingming
M
Zhang
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Aixiu
A
Wang
Department of Gastroenterology, Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, China.
Mingcui
M
Xu
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Min
M
Su
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Ming
M
Zhang
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Yuzheng
Y
Zhuge
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