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Aspafilioside B induces G2/M cell cycle arrest and apoptosis by up‐regulating H‐Ras and N‐Ras via ERK and p38 MAPK signaling pathways in human hepatoma HepG2 cells
Author(s) -
Liu Wei,
Ning Rui,
Chen RuiNi,
Huang XueFeng,
Dai QinSheng,
Hu JinHua,
Wang YuWen,
Wu LiLi,
Xiong Jing,
Hu Gang,
Guo QingLong,
Yang Jian,
Wang Hao
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22293
Subject(s) - mapk/erk pathway , apoptosis , biology , p38 mitogen activated protein kinases , cell cycle checkpoint , microbiology and biotechnology , cell cycle , kinase , signal transduction , cell growth , biochemistry
We recently establish that aspafilioside B, a steroidal saponin extracted from Asparagus filicinus , is an active cytotoxic component. However, its antitumor activity is till unknown. In this study, the anticancer effect of aspafilioside B against HCC cells and the underlying mechanisms were investigated. Our results showed that aspafilioside B inhibited the growth and proliferation of HCC cell lines. Further study revealed that aspafilioside B could significantly induce G2 phase cell cycle arrest and apoptosis, accompanying the accumulation of reactive oxygen species (ROS), but blocking ROS generation with N ‐acetyl‐ l ‐cysteine (NAC) could not prevent G2/M arrest and apoptosis. Additionally, treatment with aspafilioside B induced phosphorylation of extracellular signal‐regulated kinase (ERK) and p38 MAP kinase. Moreover, both ERK inhibitor PD98059 and p38 inhibitor SB203580 almost abolished the G2/M phase arrest and apoptosis induced by aspafilioside B, and reversed the expression of cell cycle‐ and apoptosis‐related proteins. We also found that aspafilioside B treatment increased both Ras and Raf activation, and transfection of cells with H‐Ras and N‐Ras shRNA almost attenuated aspafilioside B‐induced G2 phase arrest and apoptosis as well as the ERK and p38 activation. Finally, in vivo, aspafilioside B suppressed tumor growth in mouse xenograft models, and the mechanism was the same as in vitro study. Collectively, these findings indicated that aspafilioside B may up‐regulate H‐Ras and N‐Ras, causing c‐Raf phosphorylation, and lead to ERK and p38 activation, which consequently induced the G2 phase arrest and apoptosis. This study provides the evidence that aspafilioside B is a promising therapeutic agent against HCC. © 2015 Wiley Periodicals, Inc.