Emodin has cytotoxic and protective effects in rat C6 glioma cells: roles of Mdr1a and nuclear factor kappaB in cell survival.
1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor kappaB (NF-kappaB) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappaB activity. A confocal microscope showed that emodin induced NF-kappaB translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER- and mitochondria-induced apoptosis of C6 cells.
Kuo
Tzu-Ching
TC
Department of Microbiology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan.
Yang
Jai-Sing
JS
Lin
Meng-Wei
MW
Hsu
Shu-Chun
SC
Lin
Jen-Jyh
JJ
Lin
Hui-Ju
HJ
Hsia
Te-Chun
TC
Liao
Ching-Lung
CL
Yang
Mei-Due
MD
Fan
Ming-Jen
MJ
Wood
W G
WG
Chung
Jing-Gung
JG
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004642:Emodin / Q000494:pharmacology*; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000502:physiology*; D020011:Protective Agents; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D016328:NF-kappa B; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C085925:calcein AM; C095122:multidrug resistance protein 3; D004642:Emodin; D002118:Calcium