Aberration of the PI3K/AKT/mTOR signaling in epithelial ovarian cancer and its implication in cisplatin-based chemotherapy.
OBJECTIVE
This study was to investigate the role of the PI3K/AKT/mTOR signaling in epithelial ovarian cancer development and its mechanism in cisplatin-based chemotherapy.


METHODS
Western blot and RT-PCR were used to determine the expression of PI3K-p85 subunit at protein and mRNA levels in normal and cancerous ovarian epithelium. SKOV3/DDP cells and SKOV3/MCA (multicellular aggregates) were constructed as chemo-resistant models. The role and mechanism of AKT specific inhibitor or shRNA in different models before and after cisplatin treatment were determined by multiple cellular and molecular approaches such as cell growth assay, flow cytometry, and western blot.


RESULTS
PI3K-p85 subunit was detected in 33 out of 39 epithelial ovarian cancer specimens at protein level, but not detected in normal ovarian epithelium. A significant over-expression of PI3K-p85 subunit at mRNA level was observed in tumor tissues, and an increasing trend in advanced stage was also observed. Elevated activation of the AKT/mTOR/Survivin signaling was detected in SKOV3/DDP cells and SKOV3/MCA. Down-regulation of AKT by triciribine or shRNA transfection could attenuate cisplatin resistance through mTOR/Survivin signaling.


CONCLUSIONS
The PI3K/AKT/mTOR signaling was involved in epithelial ovarian cancer development and cisplatin-based chemotherapy, and down-regulation of AKT could be an effective adjuvant antitumor therapy.
Zhang
Hai-Yan
HY
Department of Gynecology, The Obstetrics and Gynecology Hospital, Shanghai Medical College, Fudan University, No. 419 Fangxie Road, Shanghai, PR China.
Zhang
Peng-Nan
PN
Sun
Hong
H
D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant / Q000379:methods; D002945:Cisplatin / Q000627:therapeutic use*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012263:Ribonucleosides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D002945:Cisplatin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012263:Ribonucleosides; D058570:TOR Serine-Threonine Kinases; C023764:triciribine; C546842:MTOR protein, human