title: Shengmai Formula suppressed over-activated Ras/MAPK pathway in C. elegans by opening mitochondrial permeability transition pore via regulating cyclophilin D.
abstract: 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.
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Institute of Microbiology, School of Life Sciences, Lanzhou University, Lanzhou 730000, P.R. China.
authors.forename: Menghui
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Microbiology, School of Life Sciences, Lanzhou University, Lanzhou 730000, P.R. China.
authors.forename: Dongling
authors.initials: D
authors.lastname: Liu
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Zhanxin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Fei
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Institute of Microbiology, School of Life Sciences, Lanzhou University, Lanzhou 730000, P.R. China.
authors.forename: Qingjian
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Institute of Biology, Academy of Sciences, Lanzhou 730000, Gansu province, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Gansu high throughput screening and creation center for health products, School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou 730020, P.R. China.|Institute of Microbiology, School of Life Sciences, Lanzhou University, Lanzhou 730000, P.R. China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C009252:fructus schizandrae, radix ginseng, radix ophiopogonis drug combination; D015689:Oncogene Protein p21(ras); D021983:Cyclophilins