Selenite induces redox-dependent Bax activation and apoptosis in colorectal cancer cells.
Emerging evidence suggests that selenium has chemotherapeutic potential by inducing cancer cell apoptosis with minimal side effects to normal cells. However, the mechanism by which selenium induces apoptosis is not well understood. We have investigated the role of Bax, a Bcl-2 family protein and a critical regulator of the mitochondrial apoptotic pathway, in selenite-induced apoptosis in colorectal cancer cells. We found that supranutritional doses of selenite could induce typical apoptosis in colorectal cancer cells in vitro and in xenograft tumors. Selenite triggers a conformational change in Bax, as detected by the 6A7 antibody, and leads to Bax translocation into the mitochondria, where Bax forms oligomers to mediate cytochrome c release. Importantly, we show that the two conserved cysteine residues of Bax seem to be critical for sensing the intracellular ROS to initiate Bax conformational changes and subsequent apoptosis. Our results show for the first time that selenite can activate the apoptotic machinery through redox-dependent activation of Bax and further suggest that selenite could be useful in cancer therapy.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Fang
F
Huang
Chunlai
C
Nie
Yang
Y
Yang
Wen
W
Yue
Yun
Y
Ren
Yingli
Y
Shang
Xiaohui
X
Wang
Haijing
H
Jin
Caimin
C
Xu
Quan
Q
Chen
D000494:Allosteric Regulation / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D003545:Cysteine / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria; D051336:Mitochondrial Membranes; D010084:Oxidation-Reduction / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D018038:Sodium Selenite / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
D051028:bcl-2-Associated X Protein; D018038:Sodium Selenite; D003545:Cysteine