title: Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics.
abstract: Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Shen
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lu
authors.affiliation: Nutrition & Metabolism, South Australian Health & Medical Research Institute, North Terrace, Adelaide SA5000, Australia.|Centre for Biological Sciences, Life Sciences Building, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Minfeng
authors.initials: M
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Tan
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital/Shanghai University of T.C.M, Shanghai 201203, China.|Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China.
authors.forename: Hongxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D000074624:NADPH Oxidase 1 / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013729:Terpenes; D013879:Thioredoxins; D000074624:NADPH Oxidase 1; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D010100:Oxygen; C054597:garcinol
keywords: NADPH oxidase 1; breast cancer; cambogin; reactive oxygen species; thioredoxin-1/ASK1 complex