title: Differential inhibitory potencies and mechanisms of the type I ribosome inactivating protein marmorin on estrogen receptor (ER)-positive and ER-negative breast cancer cells.
abstract: Breast cancer is the second most common cancer with a high incidence rate worldwide. One of the promising therapeutic approaches on breast cancer is to use the drugs that target the estrogen receptor (ER). In the present investigation, marmorin, a type I ribosome inactivating protein from the mushroom Hypsizigus marmoreus, inhibited the survival of breast cancer in vitro and in vivo. It evinced more potent cytotoxicity toward estrogen receptor (ER)-positive MCF7 breast cancer cells than ER-negative MDA-MB-231 cells. Further study disclosed that marmorin undermined the expression level of estrogen receptor α (ERα) and significantly inhibited the proliferation of MCF7 cells induced by 17β-estradiol. Knockdown of ERα in MCF7 cells significantly attenuated the inhibitory effect of marmorin on proliferation, suggesting that the ERα-mediated pathway was implicated in the suppressive action of marmorin on ER-positive breast cancer cells. Moreover, marmorin induced time-dependent apoptosis in both MCF7 and MDA-MB-231 cells. It brought about G2/M-phase arrest, mitochondrial membrane potential depolarization and caspase-9 activation in MCF7 cells, and to a lesser extent in MDA-MB-231 cells. Marmorin triggered the death receptor apoptotic pathway (e.g. caspase-8 activation) and endoplasmic reticulum stress (ERS, as evidenced by phosphorylation of PERK and IRE1α, cleavage of caspase-12, and up-regulation of CHOP expression) in both MCF7 and MDA-MB-231 cells. In summary, marmorin exhibited inhibitory effect on breast cancer partially via diminution of ERα and apoptotic pathways mediated by mitochondrial, death receptor and ERS. The results advocate that marmorin is a potential candidate for breast cancer therapy.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wen Liang
authors.initials: WL
authors.lastname: Pan
authors.forename: Jack Ho
authors.initials: JH
authors.lastname: Wong
authors.forename: Evandro Fei
authors.initials: EF
authors.lastname: Fang
authors.forename: Yau Sang
authors.initials: YS
authors.lastname: Chan
authors.forename: Xiu Juan
authors.initials: XJ
authors.lastname: Ye
authors.forename: Tzi Bun
authors.initials: TB
authors.lastname: Ng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005656:Fungal Proteins; D019892:eIF-2 Kinase; C506487:ESR1 protein, human; C534168:marmorin protein, Hypsizigus marmoreus