[Inhibition of mitochondrial Smac release by Akt in chemoresistant ovarian cancer cells].
OBJECTIVE
To investigate the relationship between Akt and second mitochondria-derived activator of caspases (Smac) in cisplatin (CDDP)-induced apoptosis in human ovarian cancer cells and the role of Akt in the molecular mechanism of chemoresistance in ovarian cancer.


METHODS
Chemosensitive (OV2008 and A2780s) and chemoresistant (C13* and A2780cp) ovarian cancer cell lines were treated with CDDP and subcellular Smac contents were determined by Western blot. Smac siRNA and Smac N7 peptide were transfected into OV2008 and C13* cells, respectively. CDDP-induced apoptosis was measured by flow cytometry. A2780s cells stably transfected with Akt2 (A2780s-AAkt2) and C13* cells transfected with Aktl/2 siRNA were treated with CDDP, and Smac content and apoptosis in the cells were determined to detect the changes of their chemoresistance to CDDP.


RESULTS
CDDP induced mitochondrial Smac release and apoptosis in chemosensitive cells (P < 0.05), but not resistant cells (P > 0.05). Downregulation of Smac by Smac siRNA confer resistance in OV2008 cells and Smac N7 peptide sensitized C13* cells to CDDP treatment. Overexpression of Akt2 inhibited mitochondrial Smac release and downregulation of Akt by siRNA sensitized C13* cells to CDDP treatment.


CONCLUSIONS
Smac is required in CDDP-induced apoptosis in ovarian cancer cells and overexpression of Akt inhibits mitochondrial Smac release. Akt is closely related to the chemoresistance of ovarian cancer.
Yang
Xiao-Kui
XK
Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, China.
Wang
Jian-Dong
JD
Wang
Shu-Yu
SY
Zhang
Yu-Xiang
YX
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin