Caspase-independent death of human osteosarcoma cells by flavonoids is driven by p53-mediated mitochondrial stress and nuclear translocation of AIF and endonuclease G.
Flavonoids have antioxidant and antitumor promoting effects. Rhus verniciflua Stokes (RVS) is a flavonoid-rich herbal medicine that has long been used in Korea as both a food additive and antitumor agent. It was previous reported that a purified flavonoid fraction prepared from RVS, herein named RCMF (the RVS chloroform-methanol fraction), inhibited the proliferation and induced apoptosis in human osteosarcoma (HOS) cells. This study examined the mechanisms involved in the RCMF-mediated apoptosis in HOS cells. RCMF was shown to be capable of inducing apoptosis in HOS cells by inducing p53 in the cells resulting in the decrease in Bcl-2 level, activation of Bax, and cytoplasmic release of cytochrome c, which led to the translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) into the nucleus. However, the RCMF-induced apoptosis was suppressed by transfecting the cells with antisense p53 oligonucleotides but not by treating them with a MAPK or caspase inhibitor. This suppression occurred through the regulation of Bcl-2 members as well as by preventing the nuclear translocation of the mitochondrial apoptogenic factors. Overall, it appears that p53-mediated mitochondrial stress and the nuclear translocation of AIF and EndoG are mainly required for the apoptosis induced by RCMF.
Kook
Sung-Ho
SH
Laboratory of Cell Biology in Department of Orthodontics, Institute of Oral Bioscience, Chonbuk National University, Chonju, 561-756, Korea.
Son
Young-Ok
YO
Chung
Song-Woo
SW
Lee
Seung-Ah
SA
Kim
Jong-Ghee
JG
Jeon
Young-Mi
YM
Lee
Jeong-Chae
JC
D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000166:cytology / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D005419:Flavonoids; D006801:Humans; D007723:Korea; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012516:Osteosarcoma; D029045:Rhus; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D005419:Flavonoids; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases