The roles of endoplasmic reticulum stress and Ca2+ on rhein-induced apoptosis in A-549 human lung cancer cells.
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.
Hsia
Te-Chun
TC
Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
Yang
Jai-Sing
JS
Chen
Guang-Wei
GW
Chiu
Tsan-Hung
TH
Lu
Hsu-Feng
HF
Yang
Mei-Due
MD
Yu
Fu-Shun
FS
Liu
Kuo-Ching
KC
Lai
Kuang-Chi
KC
Lin
Chin-Chung
CC
Chung
Jing-Gung
JG