title: The roles of endoplasmic reticulum stress and Ca2+ on rhein-induced apoptosis in A-549 human lung cancer cells.
abstract: Although rhein has been shown to induce apoptosis in several cancer cell lines, the mechanism of action of rhein-induced cell cycle arrest and apoptosis at the molecular level is not well known. In this study, the mechanism of rhein action on A-549 human lung cancer cells was investigated. Rhein induced G0/G1 arrest through inhibition of cyclin D3, Cdk4 and Cdk6. The efficacious induction of apoptosis was observed at 50 microM for 12 h and up to 72 h as examined by a flow cytometric method. Flow cytometric analysis demonstrated that rhein increased the levels of GADD153 and GRP78, both hallmarks of endoplasmic reticulum stress, promoted ROS and Ca2+ production, induced the loss of mitochondrial membrane potential (delta psi(m)), promoted cytochrome c release from mitochondria, promoted capase-3 activation and led to apoptosis. Rhein also increased the levels of p53, p21 and Bax but reduced the level of Bcl-2. The Ca2+ chelator BAPTA was added to the cells before rhein treatment, thus blocking the Ca2+ production and inhibiting rhein-induced apoptosis in A-549 cells. Our data demonstrate that rhein induces apoptosis in A-549 cells via a Ca2+ -dependent mitochondrial pathway.
authors.affiliation: Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Te-Chun
authors.initials: TC
authors.lastname: Hsia
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Guang-Wei
authors.initials: GW
authors.lastname: Chen
authors.forename: Tsan-Hung
authors.initials: TH
authors.lastname: Chiu
authors.forename: Hsu-Feng
authors.initials: HF
authors.lastname: Lu
authors.forename: Mei-Due
authors.initials: MD
authors.lastname: Yang
authors.forename: Fu-Shun
authors.initials: FS
authors.lastname: Yu
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Liu
authors.forename: Kuang-Chi
authors.initials: KC
authors.lastname: Lai
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung