Open AccessShengmai Formula suppressed over-activated Ras/MAPK pathway in C. elegans by opening mitochondrial permeability transition pore via regulating cyclophilin D
Author(s) -
Yan Liu,
Dejuan Zhi,
Menghui Li,
Dongling Liu,
Xin Wang,
Zhengrong Wu,
ZhanXin Zhang,
DongQing Fei,
Yang Li,
Hongmei Zhu,
Qing-Jian Xie,
Hui Yang,
Hongyu Li
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep38934
Subject(s) - mapk/erk pathway , mitochondrial permeability transition pore , mutant , phenotype , apoptosis , microbiology and biotechnology , reactive oxygen species , p38 mitogen activated protein kinases , mitochondrion , signal transduction , cyclophilin , cancer cell , oxidative stress , chemistry , biology , biochemistry , cancer , gene , programmed cell death , genetics
Since about 30% of all human cancers contain mutationally activated Ras, down regulating the over-activation of Ras/MAPK pathway represents a viable approach for treating cancers. Over-activation of Ras/MAPK pathway is accompanied by accumulation of reactive oxygen species (ROS). One approach for developing anti-cancer drugs is to target ROS production and their accumulation. To test this idea, we have employed C. elegans of let-60 (gf) mutant, which contain over-activated let-60 (the homolog of mammalian ras ) and exhibit tumor-like symptom of multivulva phenotype, to determine whether anti-oxidants can affect their tumor-like phenotype. Specifically we studied the effect of Shengmai formula (SM), a traditional Chinese medicine that has strong anti-oxidant activity, on the physiology of let-60 (gf) mutants. Unexpectedly, we found that SM treatment led to the opening of mitochondrial permeability transition pore by regulating cyclophilin D and then triggered oxidative stress and related signaling pathway activation, including p53, JNK, and p38/MAPK pathways. Finally, SM induced mitochondrial pathway of apoptosis and inhibited the tumor-like symptom of the multivulva phenotype of let-60(gf) mutants. Our results provide evidences to support that SM act as a pro-oxidant agent and could serve as a potential drug candidate for combating over-activated Ras-related cancer.