Dioscin induces caspase-independent apoptosis through activation of apoptosis-inducing factor in breast cancer cells.
Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down-regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells.
Department of Anatomy, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong Nam-Gu, Daegu, 705-717, Korea.
Eun-Ae
EA
Kim
Ji-Hoon
JH
Jang
Yun-Han
YH
Lee
Eon-Gi
EG
Sung
In-Hwan
IH
Song
Joo-Young
JY
Kim
Suji
S
Kim
Ho-Yong
HY
Sohn
Tae-Jin
TJ
Lee
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C481505:BCL2L15 protein, human; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C019357:dioscin; D020169:Caspases; D004144:Diosgenin