title: Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult.
abstract: Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs.
authors.affiliation: School of Pharmacy, National Taiwan University, No.33, Linsen S. Rd., Taipei, 100, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chan
authors.affiliation: School of Pharmacy, National Taiwan University, No.33, Linsen S. Rd., Taipei, 100, Taiwan.
authors.forename: Jui-Wei
authors.initials: JW
authors.lastname: Liang
authors.affiliation: School of Pharmacy, National Taiwan University, No.33, Linsen S. Rd., Taipei, 100, Taiwan.
authors.forename: Lih-Ching
authors.initials: LC
authors.lastname: Hsu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Chang
authors.affiliation: School of Pharmacy, National Taiwan University, No.33, Linsen S. Rd., Taipei, 100, Taiwan. shoeilee@ntu.edu.tw.
authors.forename: Shoei-Sheng
authors.initials: SS
authors.lastname: Lee
authors.affiliation: School of Pharmacy, National Taiwan University, No.33, Linsen S. Rd., Taipei, 100, Taiwan. jhguh@ntu.edu.tw.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020939:Zingiber officinale; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D012717:Sesquiterpenes; D014404:Tubulin; C403304:zerumbone; D002118:Calcium
keywords: Autophagy; ER stress; Hormone-refractory prostate cancers; Mitochondria; Tubulin